Biphenylmethane derivative and pharmacological use

ABSTRACT

The biphenylmethane derivative having the formula (I) is useful to prevent and treat hypertension and cardiac failure. ##STR1## in which R1 is hydrogen, an alkyl, a cycloalkyl, a halogenated alkyl, --S--R7, --SO2--R7, --C.tbd.C--R7 or --(CH2)p--OR7, R7 being hydrogen, an alkyl, a cycloalkyl or a halogenated alkyl, p being zero or 1, --A1=A2--A3=A4-- is --CH=CH--CH=CH--, --N=CH--CH=CH--, --CH=N--CH=CH--, --CH=CH--N=CH--, --CH=CH--CH=N-- or --CH=N--CH=N--, R2 and R3 are each hydrogen, a halogen, a lower alkyl, a lower alkoxy, a carbamoyl or cyano, R4 is hydrogen or a lower alkyl, R5 is 1H-tetrazol-5-yl, carboxyl (--COOH) or a carboxylic ester and R6 is hydrogen, a halogen, hydroxyl or a lower alkoxy, or a pharmacologically acceptable salt thereof.

This application is a divisional of application Ser. No. 07/846,950,filed on Mar. 6, 1992, now U.S. Pat. No. 5,298,518, which is a Rule 60Divisional application of Ser. No. 07/675,155, filed on Mar. 26, 1991,now abandoned, which is a continuation-in-part application of Ser. No.07/583,025, filed on Sep. 13, 1990, now U.S. Pat. No. 5,328,911, theentire contents of which are hereby incorporated by reference.

FIELD OF THE INDUSTRIAL APPLICATION

The present invention relates to a condensed imidazole compound andpharmacologically acceptable salts thereof which exhibit an excellentactivity as a pharmaceutical. More particularly, the present inventionis concerned with a novel biphenylmethane derivative andpharmacologically acceptable salts thereof useful as a therapeutic agentfor hypertension and/or a therapeutic agent for cardiac failure.

BACKGROUND OF THE INVENTION AND PRIOR ART

About 20% of the whole Japanese, i.e., about twenty million or moreJapanese are suffering from hypertension, and the hypertension is aserious risk factor of various cerebral diseases, heart diseases, etc.In practice, thiazide hypotensive diuretic agents, β-blockers, calciumantagonists, ACE inhibitors, etc., have now been clinically utilized fordrug therapy of the hypertension.

However, the origin and pathology of the hypertension are verydifferent, and it is difficult to significantly control all types ofhypertension through the use of only one drug. Further, regardingsafety, the β-blocker brings about cardiac depression and bronchialactuation as the side effects and the diuretic agent brings about sideeffects such as hyperuricemia, abnormal saccharometabolism and abnormalfat metabolism, while the ACE inhibitor brings about cough as the sideeffect.

Under the above-described circumstances, different types of betterhypotensives which exhibit their effects through various mechanisms havestill been desired.

The present inventors have made extensive and intensive studies on acompound having a nonpeptide angiotensin II antagonistic activity foryears and, as a result, have found that the following biphenylmethanederivative has an excellent activity.

Examples of the imidazole compound having an angiotensin II antagonisticactivity proposed in the art include those disclosed in Japanese PatentLaid-Open Nos. 148788/1979, 71073/1981, 71074/1981, 98270/1982,157768/1983 and 23868/1988. Further, Japanese Patent Laid-Open No.240683/1987 proposes4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acidderivatives. Any of the above-described compounds are different from thecompounds of the present invention, which will be described hereinbelow,in the structure.

SUMMARY OF THE INVENTION

The invention provides a biphenylmethane derivative having the formula(I): ##STR2## in which R1 is hydrogen, an alkyl, a cycloalkyl, ahalogenated alkyl, --S--R7, --SO2--R7, --C═C--R7 or --(CH2)p--OR7, R7being hydrogen, an alkyl, a cycloalkyl or a halogenated alkyl, p beingzero or 1, --A1═A2--A3═A4-- is --CH═CH--CH═CH--, --N═CH--CH═CH--,--CH═N--CH═CH--, --CH═CH--N═CH--, --CH═CH--CH═N-- or --CH═N--CH═N--, R2and R3 are each hydrogen, a halogen, a lower alkyl, a lower alkoxy, acarbamoyl or cyano, R4 is hydrogen or a lower alkyl, R5 is1H-tetrazol-5-yl, carboxyl (--COOH) or a carboxylic ester and R6 ishydrogen, a halogen, hydroxyl, or a lower alkoxy, or a pharmacologicallyacceptable salt thereof.

It is preferable that R5 is carboxyl or 1H-tetrazol-5-yl. R5 may be acarboxylic ester with an alkyl having 1 to 6 carbon atoms.

It is preferable that R1 is an alkyl selected from methyl, ethyl,propyl, methoxy, ethoxy and cyclopropyl; and --A1═A2--A3═A4-- is--CH═CH--CH═N--.

It is preferable that R2 is hydrogen on A1 and R3 is methyl on A3; R2 ismethyl on A1 and R3 is methyl on A3; or R2 is methyl on A1 and R3 ishydrogen on A3.

It is preferable that R4 is hydrogen and R6 is hydrogen.

The following two compounds are most preferable:

7-methyl-2-n-propyl-3-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-3H-imidazo[4,5-b]pyridine

3-[(2'-carboxylbiphenyl-4-yl)methyl]-2-cyclopropyl-7-methyl-3H-imidazo[4,5-b]pyridine

The following compounds are preferable:

2-Ethyl-7-methyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridine

3-{(2'-Carboxybiphenyl-4-yl)methyl}-7-methyl-2-n-propyl-3H-imidazo[4,5-b]pyridine

2-Cyclopropyl-7-methyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridine

3-[{5'-Chloro-2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-7-methyl-2-n-propyl-3H-imidazo[4,5-b]pyridine

3-{(2'-Carboxybiphenyl-4-yl)methyl}-2-ethylthio-7-methyl-3H-imidazo[4,5-b]pyridine

3-{(2'-Carboxy-5'-chlorobiphenyl-4-yl)methyl}-2-cyclopropyl-7-methyl-3H-imidazo[4,5-b]pyridine

2-n-Propyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridine

2-Methoxy-7-methyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridine

2-Cyclopropyl-5,7-dimethyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridine

3-{(2'-Carboxybiphenyl-4-yl)methyl}-2-cyclopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

5,7-Dimethyl-2-n-propyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridine

3-{2'-Carboxybiphenyl-4-yl)methyl}-2-n-propyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

2-Ethoxy-7-methyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridine

7-Methyl-2n-propoxy-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridine

7-Methyl-2-(1-propynyl)-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridine

2-Ethylthio-7-methyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridine

3-{(2'-Carboxybiphenyl-4-yl)methyl}-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine

2-Ethoxy-5,7-dimethyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridine

5,7-Dimethyl-2-methoxy-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3-imidazo[4,5-b]pyridine

5,7-Dimethyl-2-propoxy-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3-imidazo[4,5-b]pyridine

3-{(2'-Carboxybiphenyl-4-yl)methyl}-2-ethoxy-7-methyl-3H-imidazo[4,5-b]pyridine

3-{(2'-Carboxybiphenyl-4-yl)methyl}-2-methoxy-7-methyl-3H-imidazo[4,5-b]pyridine

3-{(2'-Carboxybiphenyl-4-yl)methyl}-2-methyl-2-n-propoxy-3H-imidazo[4,5-b]pyridine

3-{(2'-Carboxybiphenyl-4-yl)methyl}-5,7-dimethyl-2-ethoxy-3H-imidazo[4,5-b]pyridine

3-{(2'-Carboxybiphenyl-4-yl)methyl}-5,7-dimethyl-2-methoxy-3H-imidazo[4,5-b]pyridine

3-{(2'-Carboxybiphenyl-4-yl)methyl}-5,7-dimethyl-2-propoxy-3H-imidazo[4,5-b]pyridine

The invention further provides a pharmacological composition comprisinga pharmacologically effective amount of the biphenylmethane derivativeor a pharmacologically acceptable salt thereof as defined above and apharmacologically acceptable carrier.

The invention provides a method for preventing and treating hypertensionor cardiac failure by administering a pharmacologically effective amountof the biphenylmethane derivative or a pharmacologically acceptable saltthereof as defined above to a patient.

The compounds of the present invention include a biphenylmethanederivative represented by the following general formula (I) andpharmacologically acceptable salts thereof: ##STR3## wherein R¹ is ahydrogen atom, an alkyl group, a cycloalkyl group, a halogenated alkylgroup or a group represented by the formula --S--R⁷ (wherein R⁷ is ahydrogen atom, an alkyl group, a cycloalkyl group or a halogenated alkylgroup), --A¹ ═A² A³ ═A⁴ -- is a group represented by the formula--CH═CH--CH═CH--, a group represented by the formula --N═CH--CH═CH--, agroup represented by the formula --CH═N--CH═CH--, a group represented bythe formula --CH═CH--N═CH-- or a group represented by the formula--CH═CH--CH═N--, R² and R³ which may be the same or different are each ahydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxygroup, a carbamoyl group or a cyano group;

R⁴ is a hydrogen atom or a lower alkyl group;

R⁵ is a group represented by the formula ##STR4## or a carboxyl group;and

R⁶ is a hydrogen atom, a halogen atom, a hydroxyl group or a loweralkoxy group.

The term "lower alkyl group" in the above-described definition of R², R³and R⁴ on the compounds of the present invention is intended to mean astraight-chain or branched alkyl group having 1 to 6 carbon atoms, andexamples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl (amyl), isopentyl, neopentyl,tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, n-hexyl,isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl,1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl groups, among whichmethyl, ethyl, propyl, isopropyl groups, etc., are preferred and methyland ethyl groups are most desirable. Especially a methyl group is mostdesirable as the lower alkyl group in the definition of R⁴.

The term "lower alkoxy group" used in the definition of R², R³ and R⁴ isintended to mean a lower alkoxy group derived from the above-describedlower alkyl group, such as methoxy, ethoxy and n-propoxy, among which amethoxy group is most desirable.

The term "halogen atom" in the definition of R², R³ and R⁶ is intendedto mean a chlorine atom, a bromine atom, a fluorine atom or the like.

The term "alkyl group" in the definition of R¹ is preferably intended tomean a straight-chain or branched alkyl group having 1 to 10 carbonatoms. The alkyl group include, besides the above-described alkyl groupshaving 1 to 6 carbon atoms, n-heptyl, n═octyl, n-nonyl and n-decylgroups and branched alkyl groups. Among them, straight-chain or branchedalkyl groups having 1 to 8 carbon atoms are preferred, and especiallypreferred examples thereof include methyl, ethyl, n-propyl, isopropyl,n-butyl and n-pentyl groups.

The above shown preferable embodiments for R1 can apply also to R7.

The term "halogenated alkyl group" is intended to mean a group whereinany one or more hydrogen atoms of the alkyl group as defined above issubstituted by a halogen atom, especially a fluorine atom.

The term "cycloalkyl group" is intended to mean, e.g., a cycloalkylgroup having 3 to 6 carbon atoms, and cyclopropyl and cyclobutyl groupsare most desirable.

The group represented by the formula --A¹ ═A² --A³ ═A⁴ -- is intended tomean:

1 a group represented by the formula --CH═CH--CH═CH--;

2 a group represented by the formula --N═CH--CH═CH--;

3 a group represented by the formula --CH═N--CH═CH--;

4 a group represented by the formula --CH═CH--N═CH--; or

5 a group represented by the formula --CH═CH--CH═N--.

Specific examples of the portion condensed with an imidazole ring in thecompound of the present invention include the following groups: ##STR5##

In the present invention, the group represented by the formula --A¹ ═A²--A³ ═A⁴ -- is most desirably a group represented by the formula (5)--CH═CH--CH═N-- and a group represented by the formula (2)--N═CH--CH═CH-- comes next.

The above-described benzimidazole or imidazopyridine ring may besubstituted by the above-described R² and R³. Preferred examples of thesubstituent include a lower alkyl group, and the most desirablebenzimidazole or imidazopyridine ring is one mono-substituted by amethyl group.

The term "pharmacologically acceptable salt" may be any salt as far asit can be used in the present invention, and examples thereof includeammonium salt, sodium salt, potassium salt, hydrochloride, hydrobromide,methanesulfonate and sulfate.

Further, some of the above compounds may be present as the hydrate or asthe optically active isomers. It is a matter of course that thesecompounds are within the scope of the present invention.

Representative processes for preparing the compound of the presentinvention will now be described.

PREPARATION PROCESS 1

A compound represented by the general formula (1) wherein R⁵ is atetrazolyl group represented by the formula ##STR6## can be prepared bythe following process: ##STR7##

In the above-described formulae, R¹, R², R³, R⁴, R⁶ and a grouprepresented by the formula --A¹ ═A² --A³ ═A⁴ -- are each as definedabove and X is a halogen atom, a methanesulfonyloxy group or ap-toluenesulfonyloxy group.

First Step

A condensed imidazole derivative represented by the general formula (II)is condensed with a nitrile compound represented by the general formula(III) by the conventional process to prepare a compound represented bythe general formula (IV).

The above-described reaction is usually conducted in the presence of abase. Examples of the base include sodium hydride, lithium hydride,potassium carbonate, sodium carbonate, sodium alcoholate,tert-butoxypotassium, sodium hydroxide, potassium hydroxide,triethylamine and diisopropylethylamine.

Dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone,1,3-dimethyl-2-imidazolidinone, dioxane, alcohol, acetone, etc., arepreferred as the solvent for the reaction.

In the formulae, X is a halogen atom, a methanesulfonyloxy group or ap-toluenesulfonyloxy group, and the halogen atom may be chlorine,bromine, iodine or the like.

In the present process, especially preferred examples thereof includeone which comprises forming a metal salt of (l) in an aprotic polarsolvent, such as dimethylformamide, through the use of lithium hydrideor sodium hydride as a base and then conducting alkylation at 0° C. toroom temperature through the use of a biphenylmethyl halide [X=Cl, Br]and one which comprises forming a sodium salt of (l) in an alcoholthrough the use of sodium alcoholate as a base and then conductingalkylation at room temperature through the use of a biphenylmethylhalide IX=Cl, Br].

The compound represented by the general formula (III) which may be usedas a starting material in the present process can be prepared by theprocess described in, e.g., A. I. Meyers et al., J. Org. Chem., 43, 1372(1978) or Japanese Patent Laid-Open No. 23868/1988.

Second Step

The compound represented by the general formula (IV) can be reacted withan azide represented by the general formula (V) by heating in an aproticpolar solvent to prepare a compound represented by the general formula(VI).

The compound represented by the general formula (VI) can be preferablysynthesized by heating sodium azide in the presence of an amine salt,such as ammonium chloride [see J. P. Hurwitz et al., J. Org. Chem., 26,3392 (1961)], triethylamine hydrochloride [see P. P. Bernstein et al.,Synthesis, 1133 (1987)] or a pyridine hydrochloride [see H. Nakai etal., J. Med. Chem., 31, 84 (1988)] while stirring in a solvent, such asdimethylformamide, N-methylpyrrolidone or 1,3-dimethyl-2-imidazolidoneat 120° to 150° C.

When R1 is --(CH2)p--OR7, p is zero and R7 is an alkyl, the startingcompound (II) in which R1 is an alkoxy can be used in the above shownprocess. Another process comprises conducting the steps (I) and (II) byusing the starting compound (II) in which R1 is --S-alkyl, thenoxidizing the obtained compound (VI') in which R1 is --SO2-alkyl andreacting the sulfonyl compound (VI') with a compound having --R7OM, R7being an alkyl, M being a metal such as sodium and potassium, to obtaina final compound in which R1 is an alkoxy.

PREPARATION PROCESS 2

A compound represented by the general formula (I) wherein R⁵ is acarboxyl group can be prepared, e.g., by the following process: ##STR8##

In the above-described formulae, R¹, R², R³, R⁶ and a group representedby the formula --A¹ ═A² --A³ ═A⁴ -- are each as defined above,

First Step

In this step, a condensed imidazole derivative represented by thegeneral formula (II) is condensed with an ester represented by thegeneral formula (VII) by the conventional method to prepare a compoundrepresented by the general formula (VIII).

R⁸ may be any group as far as it can combine with a carboxylic acid toform an ester, and representative examples thereof include methyl andethyl groups.

The present reaction is usually conducted in the presence of a base.Preferred examples of the base include sodium hydride, lithium hydride,potassium carbonate, sodium carbonate, sodium alcoholate,tert-butoxypotassium, sodium hydroxide, potassium hydroxide,triethylamine and diisopropylethylamine.

Preferred examples of the solvent for the reaction includedimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone,1,3-dimethyl-2-imidazolidinone, dioxane, alcohol and acetone.

In the formulae, X is a halogen atom, a methanesulfonyloxy group or ap-toluenesulfonyloxy group, and the halogen atom is chloride, bromine oriodine.

In the present process, especially preferred examples thereof includeone which comprises forming a metal salt of (l) in an aprotic polarsolvent, such as dimethylformamide, through the use of lithium hydrideor sodium hydride as a base and then conducting alkylation at 0° C. toroom temperature through the use of a biphenylmethyl halide [X=Cl, Br]and one which comprises forming a sodium salt of (l) in an alcoholthrough the use of sodium alcoholate as a base and then conductingalkylation at room temperature through the use of a biphenylmethylhalide [X=Cl, Br].

Second Step

In this step, the ester represented by the general formula (VIII) ishydrolyzed to prepare one of the intended substances of the presentinvention, i.e., a compound represented by the general formula (IX).

The ester is hydrolyzed by the conventional procedure. When R⁸ is alower alkyl group such as a methyl or ethyl group, the ester can beeasily converted into a carboxylic acid, e.g., by heating the esterunder reflux in a mixed solvent comprising ethanol and an aqueous sodiumhydroxide solution. Although the hydrolysis by a base is preferred, anymethod may be applied as far as it can eliminate the protective group ofthe carboxylic acid.

As shown above, the compound of the invention can be produced by theprocess (I) in which R5 being tetrazolyl, a condensed imidazol (II) anda biphenylmethane compound (II) are reacted with each other bycondensation and cyano for R5 is converted to tetrazol with an azidcompound (V) .

When R5 is carboxyl or carboxyl ester, according to the process (II), acondensed imidazol (II) and a biphenylmethane compound (VII) arecondensed to produce a compound (VIII) having a carboxylic ester of--COOR8 for R5. The compound in which R5 is --COOH can be obtained byhydrolyzing the compound (VIII).

The effect of the compounds of the present invention will now bedescribed in more detail by way of the following examples ofpharmacological experiment.

Examples of Pharmacological Experiment 1. Experimental Method

(1) Angiotens in II contracture antagonism through the use of rabbitaortic strip

A male New Zealand white rabbit having a weight of 2 to 3 kg wasanesthetized with pentobarbital sodium, and the thoracic aorta wasremoved. A spiral preparation of the aorta having a width of 1.5 to 2 mmand a length of 15 to 20 mm was prepared therefrom and suspended in a10-ml Magnus tank containing a Krebs bicarbonate solution (Krebsbicarbonate (mM): NaCl 118.4, KCl 4.7, CaCl₂ 2.0, MgSO₄.7H₂ O 1.2,NaHCO₃.25.0, KH₂ PO₄ 1.2, glucose 11.1). 10⁻⁵ M indomethacine was addedthereto to eliminate the influence of prostaglandin. The Krebs solutionwas maintained at 37° C. and bubbled with 95% O₂ -5% CO₂. An initialtension of 1 g was applied to the strip, and the strip was allowed tostand for about 1 hr. Then, 50 mM KCl was added thereto to inducecontracture. After the contracture was stabilized, the strip was washed.The above procedure was repeated twice, and the second contracture wastaken as 100% contracture.

Thereafter, angiotensin II was accumulatively added from 10⁻¹⁰ to 3×10⁻⁶to prepare a dose-reaction curve. When studying the antagonisticactivity of the angiotensin II antagonist, a test compound was added ina concentration of 10⁻⁶ to 10⁻⁹ M 40 min before the addition of 10⁻¹⁰ Mangiotensin to observe the shift of the dose-reaction curve toward theright. The contraction was recorded on a multi-pen recorder (R-10manufactured by Rika Denki Kogyo Co., Ltd.) through a carrier amplifier(AP620G or AP621G manufactured by Nihon Koden Corp.) by making use of anisometric piezoelectric transducer (TB611T manufactured by Nihon KodenCorp.). The potency of the angiotensin II antagonist was determined bycalculating negative logarithm (-log) of a concentration of pA₂ value[i.e., a concentration of competitive antagonist which makes the doseratio of the active agent 2] through the use of Schild's equation. Theresults are given in Table 1.

(2) Inhibition of pressor reaction of angiotensin II on anesthetized rat(Wistar Kyoto) having blocked ganglions

A 9 to 25 week-old Wistar Kyoto male rat (Charles River Japan) wasanesthetized with 50 mg/kg pentobarbital sodium intraperitoneally, andthe carotid and jugular were cannulated. The carotid cannula wasconnected to a piezoelectric transducer (TP-200T), and recording wasconducted with a polygraph system (RM-6000 manufactured by Nihon KodenCorp.) through a carrier amplifier (AP-601G manufactured by Nihon KodenCorp.) and an average blood pressure measuring panel (Nihon Koden Corp.)utilizing the integration of pulse waves. 10 mg/kg of pentolinium wasadministered intravenously through the jugular cannula to conductganglion blockade. After the blood pressure was stabilized, 0.003 to 0.1or 0.3 μg/kg of angiotensin II was accumulatively administeredintravenously at such time intervals that the pressor reaction in eachdose was substantially restored (2 to 3 min), thereby preparing adose-reaction curve. Then, 0.1 to 10 mg/kg of the test compound wasadministered intravenously, and 0.03 to 1 μg/kg of angiotensin II wasagain administered intravenously 3 min after the administration of thetest compound to determine the rate of shift of the dose-pressorreaction curve toward the right. A dose (C, ED₅₀, mg/kg, i.v.) necessaryfor bringing about doubled shift of the dose-pressor reaction curvetoward the right was determined from the dose of the antagonist (A,mg/kg, i.v.) and the above-described rate of shift (B). ##EQU1## Theresults are given in Table 1.

2. EXPERIMENTAL RESULTS

The results of pharmacological experiments (1) and (2) on the compoundsof the present, invention (test compounds) are given in Table 1.

                                      TABLE 1                                     __________________________________________________________________________    Comp.                              Dose necessary for shifting about                                             doubled shift                              No. Chemical structure of test comp.                                                                          pA.sub.2                                                                         of pressor reaction of angiotensin                                            toward right (mg/kg,                       __________________________________________________________________________                                       i.v.)                                       1                                                                                 ##STR9##                    8.11                                                                            0.74                                        2                                                                                 ##STR10##                   9.08                                                                            0.15                                        3                                                                                 ##STR11##                   8.81                                                                            0.44                                        4                                                                                 ##STR12##                   8.00                                                                            1.57                                        5                                                                                 ##STR13##                  10.33                                                                            0.029                                       6                                                                                 ##STR14##                  10.04                                                                            0.019                                       7                                                                                 ##STR15##                  10.64                                                                            0.022                                       8                                                                                 ##STR16##                   8.37                                                                            0.71                                        9                                                                                 ##STR17##                   7.63                                                                            1.33                                       10                                                                                 ##STR18##                   9.18                                                                            0.42                                       11                                                                                 ##STR19##                   9.74                                                                            0.04                                       12                                                                                 ##STR20##                   9.28                                                                            0.13                                       13                                                                                 ##STR21##                   8.06                                                                            0.66                                       14                                                                                 ##STR22##                   8.53                                                                            0.35                                       15                                                                                 ##STR23##                   8.87                                                                            0.32                                       16                                                                                 ##STR24##                   8.50                                                                            0.29                                       17                                                                                 ##STR25##                   8.45                                                                            0.17                                       18                                                                                 ##STR26##                   8.67                                                                            0.075                                      19                                                                                 ##STR27##                   8.31                                                                            0.25                                       20                                                                                 ##STR28##                   8.28                                                                            0.41                                       21                                                                                 ##STR29##                  10.94                                                                            0.071                                      22                                                                                 ##STR30##                  10.62                                                                            0.040                                      23                                                                                 ##STR31##                   8.94                                                                            0.080                                      24                                                                                 ##STR32##                  10.86                                                                            0.015                                      25                                                                                 ##STR33##                   9.23                                                                            0.021                                      26                                                                                 ##STR34##                  10.58                                                                            0.0084                                     27                                                                                 ##STR35##                   9.43                                                                            0.034                                      28                                                                                 ##STR36##                   9.05                                                                            0.040                                      29                                                                                 ##STR37##                   8.47                                                                            0.060                                      30                                                                                 ##STR38##                   9.88                                                                            0.016                                      31                                                                                 ##STR39##                   9.74                                                                            0.010                                      32                                                                                 ##STR40##                   9.24                                                                            0.018                                      __________________________________________________________________________

From the above-described examples of pharmacological experiment, it isapparent that the compounds of the present invention have a remarkablyexcellent angiotensin II antagonism.

Further, compound Nos. 1, 2, 5 and 6 listed in the above-described Table1 were suspended in 0.5% MC (methylcellulose), and the suspension wasorally administered to an eight week-old male SD (Sprague Dawley) rats(4 rats per group) in a dose of 100 mg/kg/day for seven days. The ratswere observed until 24 hr after the final administration. As a result,no death was observed in all the groups to which the above-describedcompounds (compound Nos. 1, 2, 5 and 6) were administered.

Therefore, by virtue of the angiotensin II antagonism, the compounds ofthe present invention are useful for the therapy and prevention ofhypertension, useful for the therapy and prevention of cardiac failureand useful for the therapy and prevention of other diseases for whichthe angiotensin antagonism is useful. Specifically, they are useful as atherapeutic and preventive agent for hypertension such as essential,tenal, renovascular or malignant hypertension, and further as atherapeutic and preventive agent for cardiac failure. Further, asdescribed above, the compounds of the present invention have a highsafety, which renders the present invention highly valuable.

When using the compounds of the present invention as a pharmaceutical,they may be orally or parenterally administered. The dose of thecompounds of the present invention will vary depending upon the symptom;age, sex, weight and difference in the sensitivity of patients; methodof administration; time and intervals of administration, and properties,formulation and kind of pharmaceutical preparations; and kind of activeingredients, etc., so that there is no particular limitation on thedose.

In the case of oral administration, the compounds of the presentinvention are usually administered in a dose of about 1 to 1,000 mg,preferably about 5 to 500 mg per adult per day in one to three portions.In the case of injection, the dose is usually about 1 to 3,000 μg/kgpreferably about 3 to 1,000 μg/kg.

When preparing a solid preparation for oral administration, the activeingredient is blended with a vehicle and, if necessary, a binder, adisintegrator, a lubricant, a colorant, a corrigent, etc., followed bythe preparation of tablets, coated tablets, granules, powders andcapsules by the conventional procedure.

Examples of the vehicle include lactose, corn starch, sucrose, glucose,sorbitol, crystalline cellulose and silicon dioxide. Examples of thebinder include polyvinyl alcohol, polyvinyl ether, ethylcellulose,methylcellulose, acacia, tragacanth, gelatin, shellac,hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate,dextrin and pectin. Examples of the lubricant include magnesiumstearate, talc, polyethylene glycol, silica and hydrogenated vegetableoil. Any colorant of which the addition to pharmaceuticals is officiallyallowed can be used as the colorant. Examples of the corrigent includecacao powder, menthol, aromatic powder, mentha powder, borneol andpowdered cinnamon bark. It is a matter of course that a sugar coating, agelatin coating and, if necessary, suitable other coatings may beapplied on these tablets and granules.

When preparing injections, a pH modifier, a buffering agent, asuspending agent, a solubilizing agent, a stabilizer, a tonicity agent,a preservative, etc., are added to the active ingredient, followed bythe preparation of intravenous, subcutaneous and intramuscularinjections according to the conventional procedure. In this case, thesepreparations may be lyophilized by the conventional procedure.

Examples of the suspending agent include methylcellulose, Polysorbate80, hydroxyethylcellulose, gum arabic, powdered trangcanth, sodiumcarboxymethylcellulose and polyoxyethylene sorbitan monolaurate.

Examples of the solubilizing agent include polyoxyethylene hydrogenatedcastor oil, Polysorbate 80, nicotinamide, polyoxyethylene sorbitanmonolaurate, Macrogol,-and ethyl esters of castor oil fatty acids.

Examples of the stabilizer include sodium sulfite, sodium metasulfiteand ether, and examples of the preservative include methylp-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenol, cresoland chlorocresol.

Representative compounds of the present invention will now be describedby way of the following Examples. It is needless to say that the presentinvention is not limited to these only.

Apart from the Examples, Preparation Examples will be given for thepreparation of a starting material used in the preparation of the objectsubstance of the present invention.

In the chemical structural formulae, Me is a methyl group, Et an ethylgroup, n-Pr a n-propyl and n-Bu a n-butyl group.

PREPARATION EXAMPLE 1

4-Chloro-2-methoxybenzoyl chloride ##STR41##

120 ml of thionyl chloride was dropwise added at room temperature to 75g of 4-chloro-2-anisic acid, and the mixture was stirred at roomtemperature for 12 hr. The reaction mixture was concentrated forcrystallization. The crystal was used for the subsequent reactionwithout purification.

PREPARATION EXAMPLE 2

2-(4-Chloro-2-methoxyphenyl)-4,4-dimethyloxazoline ##STR42##

80 g of 2-amino-2-methyl-1-propanol was dissolved in 350 ml of methylenechloride, and the solution was cooled to -5° C.4-Chloro-2-methoxybenzoyl chloride was dissolved in 180 ml of methylenechloride and then slowly dropwise added to the cooled solution. Afterthe dropwise addition, the mixture was stirred at room temperature for 2hr. The reaction mixture was filtered, and the crystal was washed withmethylene chloride. Dilute hydrochloric acid was added to the filtrateand then subjected to phase separation to get an organic phase. Theorganic phase was dried over anhydrous magnesium sulfate and thenconcentrated. 120 ml of thionyl chloride was slowly dropwise added atroom temperature to 106 g of the resultant oleaginous substance. Themixture was stirred for an additional 1 hr and then concentrated. Waterwas added to the concentrate for dissolution, and an aqueous sodiumhydroxide solution was added to the solution to adjust the pH value to11. Chloroform was added thereto, and the mixture was extracted, driedover anhydrous magnesium sulfate and then concentrated. The residue waspurified by column chromatography (chloroform). The yield was 62.3 g.

NMR(90 MHz, CDCl₃, δ value): 7.65(d,1H,J=8 Hz), 7.00˜6.81(m,2H), 4.05(s,2H), 3.87(s,3H),1.39(s,6H)

PREPARATION EXAMPLE 3

2-(4-Chloro-4'-methylbiphenyl-2-yl)-4,4-dimethyloxaline ##STR43##

A THF solution (450 ml) of 46.0 g of 4-bromotoluene was dropwise addedto 6.38 g of magnesium in a nitrogen stream. After heating under refluxfor 40 min, the reaction mixture was dropwise added at room temperatureto a THF solution (260 ml) of 30 g of2-(4-chloro-2-methoxyphenyl)-4,4-dimethyloxazoline. The mixture wasstirred at room temperature for 2 hr and then cooled, and an aqueousammonium chloride was added thereto. The mixture was extracted withethyl acetate, and the extract was washed with a dilute sodium hydroxidesolution and a saline solution, dried over anhydrous magnesium sulfateand then concentrated to prepare 38 g of the title compound in a crudeform.

NMR(90 MHz, CDCl₃, δ value): 7.64(d,1H,J=8Hz),7.40˜7.00(m,6H),3.79(s,2H),2.38(s,3H),1.29(s,6H)

PREPARATION EXAMPLE 4

4-Chloro-2-(4-methylphenyl)benzoic acid ##STR44##

500 ml of 4.6N hydrochloric acid was added to 38 g of2-(4-chloro-4'-methylbiphenyl-2-yl)-4,4-dimethyloxazoline, and themixture was heated under reflux for 36 hr. After cooling the refluxedsolution was extracted with a mixed solvent comprising ether and ethylacetate, washed with water, dried over anhydrous magnesium sulfate andthen concentrated. The residue was recrystallized from THF-isopropylether-hexane to give 17.5 g of the title compound.

m.p. (°C.): 143.5˜146

NMR (90 MHz, CDCl₃, δ value): 9.30 (bs, 1H), 7.87 (1H, d, J=8 Hz),7.46˜7.20 (m, 2H), 7.18 (s, 4H), 2.38 (s, 3H)

The following starting materials used for synthesizing the compounds ofthe present invention were prepared according to the process describedin Preparation Examples 1 to 4.

(1) 3-Methoxy-2-(4-methylphenyl)benzoic acid

m.p. (°C.): 180.5˜181

NMR(90 MHz, CDCl₃, δ value): 9.40(bs, 1H), 7.55˜6.98 (m, 3H), 7.06 (s,4H), 3.73 (s, 3H), 2.38 (s, 3H)

(2) 4-Methoxy-2-(4-methylphenyl)benzoic acid

m.p. (°C.): 176˜179

NMR(90 MHz, CDCl₃, δ value): 9.40 (bs, 1H), 7.96 (d, 1H, J=8 Hz), 7.18(s, 4H), 6.97˜6.56 (m, 2H), 3.84 (s, 3H), 2.39 (s, 3H)

(3) 5-Chloro-2-(4-methylphenyl)benzoic acid

m.p. (°C.): 143˜145

NMR (90 MHz, CDCl₃, δ value): 10.05 (bs, 1H), 7.88 (d, 1H, J=2 Hz), 7.49(dd, 1H, J=2 Hz, 8 Hz), 7.26 (d, 1H, J=8 Hz), 7.16 (s, 4H), 2.37 (s, 4H)

(4) 5-Methoxy-2-(4-methylphenyl)benzoic acid

NMR (90 MHz, CDCl₃, δ value): 9.40 (bs, 1H), 7.37˜6.82 (m, 7H), 3.81 (s,3H), 2.32 (s,3H)

PREPARATION EXAMPLE 5

4-Chloro-2-(4-methylphenyl)benzamide ##STR45##

40 ml of thionyl chloride was dropwise added to 12.4 g of4-chloro-2-(4-methylphenyl)benzoic acid, and the mixture was heatedunder reflux for 2 hr. The reaction mixture was concentrated. In thisprocedure, toluene was added to distill off the thionyl chloride as muchas possible. The residue was dissolved in 120 ml of tetrahydrofuran, andan ammonia gas was blown into the solution at an internal temperature of-12° to -5° C. Water and chloroform were added to the reaction mixture,and the mixture was subjected to phase separation. The organic phase waswashed with water and then dried over anhydrous magnesium sulfate. Thedried organic phase was concentrated and then recrystallized fromtetrahydrofuran-isopropyl ether to give 9.1 g of the title compound.

m.p. (°C.): 162˜163.5

NMR(90 MHZ, CDCl₃, δ value): 7.72(d,1H,J=8 Hz),7.42˜7.08(m,2H),7.16(s,4H),2.39(s,3H)

PREPARATION EXAMPLE 6

4-Chloro-2-(4-methylphenyl)benzonitrile ##STR46##

26 ml of thionyl chloride was dropwise added to 8.9 g of4-chloro-2-(4-methylphenyl) benzamide, and the mixture was heated underreflux for 2.5 hr. Excess thionyl chloride was distilled off as much aspossible by making use of toluene. The residue was recrystallized from amixed solvent of tetrahydrofuran-isopropyl ether-n-hexane to prepare 7.2g of a product.

m.p. (°C.): 48°˜50° C.

NMR (90 MHz, CDCl₃, δ value): 7.66 (d, 1H, J=8 Hz), 7.60˜7.15 (m, 6H),2.38 (s,3H)

The following starting materials used for synthesizing the compounds ofthe present invention were prepared according to the process describedin Preparation Examples 5 to 6.

(1) 3-Methoxy-2-(4-methylphenyl)benzonitrile

m.p. (°C.): 94.5˜96

NMR(90 MHz, CDCl₃, δ value): 7.45˜7.10 (m, 7H), 3.78 (s, 3H), 2.41 (s,3H)

(2) 4-Methoxy-2-(4-methylphenyl)benzonitrile

m.p. (°C.): 121˜123

NMR (90 MHz, CDCl₃, δ value): 7.66 (d, 1H, J=8 Hz), 7.50˜7.15 (m, 4H),7.00 ˜6.78 (m,2H), 3.88 (s, 3H), 2.42 (s, 3H)

(3) 5-Chloro-2-(4-methylphenyl)benzonitrile

m.p. (°C.): 111˜113.5

NMR (90 MHz, CDCl₃, δ value): 7.75˜7.15 (s, 7H), 2.42(s, 3H)

(4) 5-Methoxy-2-(4-methylphenyl)benzonitrile

m.p. (°C.): 152˜155

NMR (90 MHz, CDCl₃, δ value): 7.45˜6.93 (m, 7H), 3.91 (s, 3H), 2.44 (s,3H)

PREPARATION EXAMPLE 7

2-(4-Bromomethylphenyl)4-chlorobenzonitrile ##STR47##

6.83 g of 4-chloro-2-(4-methylphenyl)benzonitrile, 5.34 g ofN-bromosuccinimide and 0.1 g of α,α'-azobis(isobutyronitrile) wereheated in 220 ml of carbon tetrachloride under reflux for 2 hr. Thesuccinimide was removed by filtration, and the filtrate wasconcentrated. The residue was crystallized from a mixed solvent oftetrahydrofuran-isopropyl ether. The yield was 5.6 g.

m.p. (°C.): 122˜125

NMR (90 MHz, CDCl₃, δ value): 7.69(d,2H,J=8 Hz),7.52 (s, 4H), 7.48(d,1H, J=2 Hz), 7.40(dd, 1H, J=2 Hz, 8 Hz), 4.53 (s, 2H)

PREPARATION EXAMPLE 8

Methyl 2-(4-methylphenyl)benzoate ##STR48##

6 g of sulfuric acid in 12 ml of methanol was added to 3.2 g of2-(4-methylphenyl)benzoic acid [see A. I. Meyers et al., J. Org. Chem.,43, 1372 (1978)], and the mixture was heated under reflux for 8 hr. Therefluxed solution was cooled, poured into ice water, weakly alkalifiedwith aqueous ammonia and extracted with ether. The extract was driedover anhydrous magnesium sulfate. The dried extract was concentrated,and the residue was recrystallized from n-hexane to prepare 2.4 g of thetitle compound.

m.p. (°C.): 54˜57

PREPARATION EXAMPLE 9

Methyl 2-(4-bromomethylphenyl)benzoate ##STR49##

2.0 g of methyl 2-(4-methylphenyl)benzoate, 1.6 g of N-bromosuccinimideand 0.05 g of α,α'-azobis(isobutyronitrile) were heated in 110 ml ofcarbon tetrachloride under reflux for 2 hr. The succinimide was filteredoff. The filtrate was concentrated, and the residue was recrystallizedfrom a mixed solvent of n-hexane-isopropyl ether to prepare 1.6 g of thetitle compound.

m.p. (°C.): 50˜51

PREPARATION EXAMPLE 10

(1) 2-Amino-4-n-propylpyridine ##STR50##

75 g (0.62M) of 4-n-propylpyridine and 28 g (0.73M) of sodium amide wereadded to 250 ml of xylene, and the mixture was heated under reflux for10 hr. Water was added in small portions to the reaction mixture underice cooling to decompose excess sodium amide, and the reaction mixturewas extracted with ethyl acetate, dried over magnesium sulfate and thenpurified by column chromatography (dichloromethanemethanol 50:1÷20:1).The yield was 33 g. (blackish purple solid)

NMR (90 MHz, CDCl₃, δ value); 7.90 (d, 1H, J=8 Hz), 6.46 (dd, 1H, J=5Hz, 1Hz), 6.28 (d, 1H, J=1 Hz), 4.50 (bs, 2H), 2.44 (t, 2H, J=7 Hz),1.82˜1.30(m, 2H), 0.94 (t, 3H, J=7 Hz)

(2) 2,3-Diamino-4-n-propylpyridine ##STR51##

33 g (0.24M) of 2-amino-4-n-propylpyridine was added in small portionsto 120 ml of concentrated sulfuric acid at an internal temperature of25° C. or below under ice cooling. 17 ml (0.38M) of concentrated nitricacid was dropwise added thereto at an internal temperature of 20° C. orbelow under ice cooling. After the completion of the dropwise addition,the cooling bath was removed, and the mixture was allowed to stand atroom temperature for 1 hr. The temperature was gradually raised, and themixture was stirred at 95° C. for 1 hr. The reaction mixture was pouredonto ice, and concentrated aqueous ammonia was added thereto foralkalification, followed by extraction with ethyl acetate. The extractwas dried over magnesium sulfate, and the solvent was distilled off invacuo to prepare a solid mixture of 2-amino-3-nitro-4-n-propylpyridinewith 2-amino-5-nitro-4-n-propylpyridine.

This mixture was suspended in methanol and catalytically hydrogenated inthe presence of palladium carbon. The palladium carbon was removed byfiltration, and the solvent was distilled off in vacuo. The residue waspurified by silica gel chromatography. The yield was 2.6 g (browncrystal).

NMR (90 MHz, CDCl₃, δ value): 7.55(d, 1H,J=8 Hz),6.50(d, 1H,J=8 Hz),3.80(bs, 4H), 2.47 (t, 2H, J=7 Hz), 1.88˜1.40(m, 2H), 1.00(t,3H, J=7 Hz)

(3) 2-Ethyl-7-n-propyl-imidazo[4,5-b]pyridine ##STR52##

2.6 g (0.017M) of 2,3-diamino-4-n-propylpyridine and 1.4 ml (0.019M) ofpropionic acid were added to 15 ml of phosphoric acid, and the mixturewas heated at 140° to 150° C. for 20 hr. It was cooled to roomtemperature, poured into a cold aqueous NaOH solution and then extractedwith ethyl acetate. The extract was dried over magnesium sulfate, andthe solvent was distilled off in vacuo to prepare a substantially purebrown oleaginous intended product. The yield was 2.9 g (this compoundwas used as a starting material in the preparation of the following rawmaterial (29)) .

NMR(90 MHz, CDCl₃, δ value): 8.10 (d, 1H, J=8 Hz), 7.02 (d, 1H, J=8 Hz),3.10 (q, 4H, J=7 Hz), 2.08˜1.68 (m, 2H), 1.56 (t,3H, J=7 Hz), 1.04 (t,3H, J=7 Hz)

PREPARATION EXAMPLE 11

2-Cyclopropyl-7-methyl-3H-imidazo[4,5-b]pyridine ##STR53##

30 ml of cyclopropanecarboxylic acid and 70 ml of phosphoric acid (85%)were added to 15 g of 2,3-diamino-4-methylpyridine, and the mixture wasstirred at an internal temperature of 130° C. for 12 hr. The reactionmixture was cooled, poured into a solution of 140 g of potassiumhydroxide in 420 ml of water and then extracted with chloroform. Theextract was dried over anhydrous magnesium sulfate and thenconcentrated. The residue was purified by column chromatography(chloroform : ethanol=97:3). The yield was 14.1 g, and the product wasrecrystallized from ethyl acetate-isopropyl ether to prepare the titlecompound in a pure form having a melting point of 203° to 204° C.

NMR (90 MHz, CDCl₃, δ value): 8.16(d, 1H,J=8 Hz), 7.00(d, 1H,J=8Hz),2.68 (s,3H) ,2.50˜2.10(m, 1H), 1.40˜1.12(m, 4H)

PREPARATION EXAMPLE 12

The following compounds were prepared according to the process describedin the above-described Preparation Example 10(3) and Preparation Example11. These compounds are used as a starting material in the process forpreparing the compounds of the present invention. ##STR54## NMR(90 MHz,CDCl₃ : δ value): 8.15(d, 1H,J=5 Hz), 7.02(d, 1H,J=5Hz),3.06 (t, 2H, J=7Hz), 2.68 (s, 3H), 2.14˜1.70 (m, 2H), 1.70˜1.10(m, 2H), 0.97 (t, 3H, J=7Hz) ##STR55## NMR(90 MHz, CDCl₃, δ value): 13.01 (bs; 1H) ,8.22(s, 1H),3.01 (t,2H,J=7 Hz), 2.72 (s, 3H), 2.20˜1.70 (m, 2H), 1.08 (t, 3H, J=7Hz) ##STR56##

NMR (90 MHz, CDCl₃, δ value): 8.12 (d, 1H, J=1Hz), 7.81 (d, 1H, J=1Hz),3.02 (t, 2H, J=7 Hz), 2.49(s,3H),2.20˜1.72(m,2H),1.08(s,3H) ##STR57##NMR(90 MHz, CDCl₃, δ value): 12.80(bs, 1H), 2.31 (d, 1H, J=2Hz), 8.12(d, 1H, J=2Hz), 2.86 (q, 2H, J=7 Hz), 1.33 (t, 3H, J=7 Hz) ##STR58## NMR(90 MHz, CDCl₃, δ value): 8.24 (d, 1H, J=8 Hz), 7.06 (d, 1H, J=8 Hz),4.00 (quint, 1H, J=8 Hz), 2.75 (s, 3H), 2.86˜1.96 (m,6H) ##STR59## NMR(400 MHz, CDCl₃, δ value): 8.15(d, 1H,J=8 Hz) ,7.01 (d, 1H,J=5 Hz) ,3.40(q, 2H, J=3Hz), 2.66 (s, 3H), 1.48 (t, 3H, J=8 Hz) ##STR60## NMR (90MHz, CDCl₃, δ value): 8.14 (d, 1H, J=5 Hz), 6.67 (d,1H,J=8 Hz), 4.10 (s,3H), 3.00 (t, 2H, J=8 Hz), 2.20˜1.70 (m, 2H), 1.08(t,3H,J=8 Hz)##STR61## NMR (90 MHz, CDCl₃, (δ value): 8.23 (d, 1H, J=5 Hz), 7.02 (d,1H, J=5 Hz), 4.88 (s, 2H), 3.57 (s, 3H), 2.70 (s, 3H) ##STR62## NMR (90MHz, CDCl₃, δ value): 8.10 (d, 1H, J=5 Hz), 7.10˜6.60 (m, 2H), 6.46 (dd,1H, J=15 Hz, 1Hz), 2.58 (s, 3H), 1.99 (dd, 3H, J=6 Hz, 1 Hz) ##STR63##NMR (400 MHz, CDCl₃, δ value): 8.34˜8.02 (m, 3H), 7.64˜7.36 (m, 3H),7.03 (d, 1H, J=5 Hz), 2.64 (s, 3H) ##STR64## NMR (400 MHz, CDCl₃, δvalue): 8.04 (d, 1H, J=5 Hz), 6.92 (d, 1H, J=5 Hz) , 3.50˜3.00 (m, 1H),2.52 (m, 3H), 2.24˜1.46 (m, 8H) ##STR65## NMR (400 MHz, DMSO-d₆, δvalue): 8.97 (1H, s), 8.84 (1H, s), 2.87 (2H, t, J=8 Hz), 1.88˜1.78 (2H,m) , 0.96 (3H, t, J=8 Hz) ##STR66## NMR (400 MHz, CDCl₃, δ value): 6.90(1H, s), 2.98 (2H, t, J=8 Hz), 2.66 (3H, s), 2.65 (3H, s), 1.94˜1.85(2H, m), 1.037 (3H, t, J=8 Hz) ##STR67## NMR (400 MHz, CDCl₃, δ value):6.84 (1H, s), 2.66 (3H, s), 2.58 (3H, s), 2.21˜2.15 (1H, m), 1.26˜1.22(2H, m), 1.12˜1.07 (2H, m)

PREPARATION EXAMPLE 13

2-n-Butyl-1-{(5'-chloro-2'-cyanobiphenyl-4-yl)methyl}benzimidazole##STR68##

522 g of 2-n-butylbenzimidazole was dissolved in 10 ml ofdimethylformamide and dropwise added to 130 g of sodium hydride. Themixture was stirred at room temperature for 30 min, and 920 mg of2-(4-bromomethylphenyl)-4-chlorobenzonitrile dissolved in 10 ml ofdimethylformamide was dropwise added thereto. The mixture was stirred atroom temperature for 10 min, and the reaction mixture was filtered. Thefiltrate was concentrated and water and ethyl acetate were added to theresidue. The organic phase was separated, dried over anhydrous magnesiumsulfate and then concentrated. The residue was purified by columnchromatography (chloroform: ethanol=98:2) (yield: 1.12 g).

NMR(90 MHz, CDCl₃, δ value): 7.82˜6.95 (m, 11H), 5.38 (s, 2H), 2.83 (t,2H, J=7 Hz), 2.00˜1.15 (m, 2H), 0.92 (t, 3H, J=7 Hz)

PREPARATION EXAMPLE 14

3-{(2'-Cyanobiphenyl-4-yl)methyl}-2-ethyl-3H imidazo[4,5-b]pyridiene##STR69##

735 mg of 2-ethylimidazo[4,5b]pyridine was dissolved in 15 ml ofdimethylformamide and dropwise added to 220 mg of sodium hydride. Themixture was stirred at room temperature for 30 min, and 1.4 g of2-(4-bromomethylphenyl) benzonitrile dissolved in 15 ml ofdimethylformamide was dropwise added thereto. The mixture was stirred atroom temperature for 10 min and the reaction mixture was filtered. Thefiltrate was concentrated and water and ethyl acetate were added to theresidue. The organic phase was separated, dried over anhydrous magnesiumsulfate and then concentrated. The residue was purified by silica gelcolumn chromatography, and eluation was conducted by gradually changingthe eluent from 2% ethanol-98% chloroform to 5% ethanol-95% chloroformto separate regioisomers. The first eluted fraction was the intendedtitle compound (yield: 800 mg).

NMR (90 MHz, CDCl₃, δ value): 8.34 (dd, 1H, J=1 Hz, 5 Hz), 8.02 (dd, 1H,J=1Hz, 8 Hz), 7.78˜6.95 (m, 9H), 5.55 (s, 2H), 2.87 (q, 2H, J=7 Hz),1.42 (t, 3H, J=7 Hz)

The next eluted fraction was1-{(2'-cyanobiphenyl-4-yl)methyl}-2-ethyl-1H-imidazo[4,5-b]pyridine(yield: 200 mg). ##STR70## NMR (90 MHz, CDCl₃, δ value): 8.53(dd, 1H,J=1Hz,5 Hz), 7.82˜6.90(m, 10H), 5.41 (s,2H) ,2.93(q,2H,J=7 Hz), 1.47(t,3H,J=7 Hz)

The third eluted fraction was4-{(2'-cyanobiphenyl-4-yl)methyl}-2-ethyl-4H-imidazo[4,5-b]pyridine(yield: 570 g). ##STR71## NMR (90 MHz, CDCl₃, δ value): 8.07 (d, 1H, J=7Hz), 7.82˜7.26 (m, 9H), 7.02 (dd, 1H, J=7 Hz, 7 Hz), 5.88 (s, 2H), 3.09(q, 2H, J =7 Hz), 1.49 (t, 3H, J=7 Hz)

The structures of the regioisomers were determined by measuring the NOE(nuclear overhouser effect).

PREPARATION EXAMPLE 15

(a)2-n-Butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-1H-imidazo[4,5-c]pyridineand (b) 2-n-butyl-3-[(2'-cyanobiphenyl-4-yl )methyl]-3H-imidazo[4,5-c]pyridine ##STR72##

6.0 g (0.37M) of 2-n-butylimidazo[4,5-c]pyridine and 10 g (0.037M) of2-(4-bromomethylphenyl)benzonitrile were suspended in 50 ml ofdimethylformamide, and 1.6 g (0.040M) of sodium hydride was addedthereto at once at room temperature under stirring. 30 min after theaddition, water was added thereto, and the mixture was extracted withethyl acetate. The extract was dried over magnesium sulfate. The solventwas distilled off in vacuo, and the residue was purified by silica gelchromatography. The first eluted fraction was2-n-butyl-3-[2'-cyanobiphenyl-4-yl)methyl]-3H-imidazo[4,5-c]pyridine(yield 160 mg, brown oleaginous substance), and the next eluted fractionwas2-n-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-1H-imidazo[4,5-c]pyridine(yield 200 mg, brown oleaginous substance).

(a) NMR (90 MHz, CDCl₃, δ value): 8.60 (s, 1H), 8.38 (d, 1H, J=5 Hz),7.82˜7.00 (m, 9H), 5.46 (s, 2H), 2.92 (t,2H, J=7 Hz), 2.08 ˜1.30 (m,4H), 0.96 (t, 3H, J=7 Hz).

(b) NMR (90 MHz, CDCl₃, δ value): 9.04 (s, 1H),8.32 (d, 1H,J=8 Hz),7.80˜7.00 (m, 9H), 5.40 (s, 2H), 2.90 (t, 2H, J=7 Hz), 2.07 ˜1.20 (m,4H), 0.96 (t, 3H, J=7 Hz)

PREPARATION EXAMPLE 16

The following compounds usable as a starting material for synthesizingthe compounds of the present invention were prepared according to theprocess described in Preparation Examples 13 to 15.

The chemical structural formulae of the prepared compounds will bedescribed below. ##STR73## NMR (90 MHz, CDCl₃, δ value): 7.85˜7.62 (m,1H), 7.45˜6.85 (m, 10H), 5.40 (s, 2H), 3.75 (s, 3H), 2.86 (t, 2H, J=7Hz), 2.02 ˜1.10 (m, 4H), 0.92 (t, 3H, J=7 Hz) ##STR74## NMR (90 MHz,CDCl₃, δ value): 8.34 (dd, 1H, J=1 Hz, 5 Hz), 8.01 (dd, 1H, J=1 Hz, 8Hz), 7.78˜7.06 (m, 9H), 5.56 (s, 2H), 2.83 (t, 2H, J=7 Hz), 2.00˜1.56(m, 2H), 1.54˜1.05 (m, 4H), 0.87 (t, 3H, J=7 Hz) ##STR75## NMR (90 MHz,CDCl₃, δ value): 7.86˜7.00 (m, 11H), 5.40 (s, 2H), 2.86 (t, 2H, J=7 Hz),2.03˜1.15(m, 4H), 0.93 (t, 3H, J=7 Hz) ##STR76## NMR (90 MHz, CDCl₃, δvalue): 8.33(dd, 1H, J=1 Hz,5 Hz) ,8.01 (dd, 1H, J=1 Hz, 8 Hz),7.74˜7.05 (m, 8H), 5.56 (s, 2H), 2.83 (t, 2H, J=7 Hz), 2.00˜1.15 (m,4H), 0.92 (t, 3H, J=7 Hz) ##STR77## NMR (90 MHz, CDCl₃, δ value): 8.34(dd, 1H, J=1 Hz,5 Hz) ,8.02(dd, 1H, J=1 Hz, 8 Hz), 7.72˜7.05 (m, 8H),5.56 (s, 2H), 2.84 (t, 2H, J=7 Hz), 2.00˜1.17 (m, 4H), 0.92 (t, 3H, J=7Hz) ##STR78## NMR(90 MHz, CDCl₃, δ value): 8.34 (dd, 1H, J=1 Hz, 5 Hz),8.01 (dd, 1H, J=1 Hz, 8 Hz), 7.75˜7.05 (m, 6H), 7.00˜6.82 (m, 2H), 5.56(s, 2H), 3.87 (s, 3H), 2.85 (t, 2H, J=7 Hz), 2.02˜1.15(m, 4H),0.93(t,3H, J=7 Hz) ##STR79## NMR(90 MHz, CDCl₃, δ value): 7.83˜7.35 (m,4H), 7.33˜6.98 (m, 5H), 6.98 ˜6.77 (m, 2H), 5.40 (s, 2H), 3.87 (s, 3H),2.87 (t, 2H, J=8 Hz), 2.06˜1.22 (m, 4H), 0.94 (t, 3H, J=7 Hz) ##STR80##NMR (90 MHz, CDCl₃, δ value): 8.34 (dd, 1H, J=1Hz, 5 Hz), 8.02 (dd, 1H,J=1 Hz, 8 Hz), 7.75˜7.12 (m, 8H), 5.57 (s, 2H), 2.82 (t, 2H,J=7 Hz),2.10˜1.62(m,2H), 1.02(t,3H,J=7 Hz) ##STR81## NMR (90 MHz, CDCl₃, δvalue): 8.34 (dd, 1H,J=1 Hz,5 Hz),8.01 (dd, 1H,J=1 Hz, 8 Hz), 7.80˜7.00(m, 8H), 5.56 (s, 2H), 2.82 (t, 2H, J=7 Hz), 2.12˜1.58 (m, 2H), 1.02 (t,3H, J=7 Hz) ##STR82## NMR (90 MHz, DMSO-d₆, δ value): 7.85˜7.00 (m,12H), 5.39 (s, 2H), 2.84 (t, 2H, J=7 Hz), 2.04˜1.20 (m, 4H), 0.92 (t,3H, J=7 Hz) ##STR83## NMR (90 MHz, CDCl₃, δ value): 7.80˜6.70 (m, 11H),5.36 (s, 2H), 2.85 (t, 2H, J=7 Hz), 2.04˜1.20(m, 4H), 0.95 (t, 38, J=7Hz) ##STR84## NMR (90 MHz, CDCl₃, δ value): 7.80˜6.70 (m, 11H), 5.32 (s,2H), 2.86 (t, 2H, J=7 Hz), 2.04˜1.24 (., 4H), 0.96 (t, 3H, J=7 Hz)##STR85## NMR (90 MHz, CDCl₃, δ value): 8.30(dd, 1H, J=8 Hz, 1Hz), 7.98(dd, 1H, J=8 Hz, 1Hz), 7.78˜7.04 (m, 9H), 5.54 (s, 2H), 2.86 (t, 2H, J=7Hz), 2.02˜1.22 (m, 4H), 0.94 (t, 3H, J=7 Hz) ##STR86## NMR (90 MHz,CDCl₃, δ value): 8.28 (dd, 1H, J=8 Hz, 1 Hz), 7.96 (dd, 1H, J=8 Hz,1Hz), 7.50˜6.96 (m, 8H), 5.52 (s, 2H), 3.76 (s, 3H), 2.84 (t, 2H, J=7Hz), 2.04˜1.16 (m, 4H), 0.92(t,3H,J=7 Hz) ##STR87## NMR (90 MHz, CDCl₃,δ value): 8.30 (dd, 1H, J=5 Hz, 1Hz), 7.96 (dd, 1H, J=8 Hz, 1Hz),7.80˜7.08 (m, 9H), 5.54 (s, 2H), 2.84 (t,2H,J=7 Hz) ,2.10˜1.66(m,2H),1.04 (t, 3H, J=7 Hz) ##STR88## NMR (90 MHz, CDCl₃, δ value):7.84˜7.60(m, 1H), 7.52˜6.98(m, 10H), 5.36 (s, 2H), 3.84 (s, 3H), 2.88(t, 2H, J=7 Hz), 2.04 ˜1.20 (m, 4H), 0.95 (t, 3H, J=7 Hz) ##STR89## NMR(90 MHz, CDCl₃, δ value): 8.49(dd, 1H,J=8 Hz, 1Hz) ,8.07˜7.01 (m, 10H),5.48 (s, 2H), 2.90(t, 2H, J=7 Hz), 2.04˜1.10 (m, 4H), 0.93(t,3H, J=7 Hz)##STR90## NMR (90 MHz, CDCl₃, δ value): 8.16 (d, 1H, J=5 Hz), 7.80˜7.06(m, 8H), 7.00 (d, 1H, J=5 Hz), 5.54 (s, 2H), 2.85 (t, 2H, J=7 Hz), 2.70(s, 3H), 2.04˜1.60 (m, 2H), 1.02 (t, 3H, J=7 Hz) ##STR91## NMR (90 MHz,CDCl₃, δ value): 8.16(d, 1H,J=8 Hz),7.76˜7.08(m,8H),7.00 (d, 1H, J=8Hz), 5.54 (s, 2H), 2.88 (q, 2H, J=7 Hz), 2.72 (s, 3H), 1.40 (t, 3H, J=7Hz) ##STR92## NMR (90 MHz, CDCl₃, δ value): 8.17(d,1H J=5 Hz)7.80˜7.10(m, 8H) 7.02 (d, 1H, J=5 Hz), 5.52 (s, 2H), 2.72 (s, 3H), 2.63(s,3H) ##STR93## NMR (90 MHz, CDCl₃, δ value): 8.16 (d, 1H, J=5 Hz),7.80˜7.08 (m, 8H), 7.00 (d, 1H, J=5 Hz), 5.52 (s, 2H), 2.86 (t, 2H, J=6Hz), 1.96˜1.16(m,4H), 0.92(t,3H,J=6 Hz) ##STR94## NMR (90 MHz, CDCl₃, δvalue): 8.23 (d, 1H, J=8 Hz), 7.80˜6.99(m, 14H), 5.60 (s,2H), 2.76(s,3H)##STR95## NMR (90 MHz, CDCl₃, δ value): 8.12(d, 1H,J=8 Hz),7.80˜7.10(m,8H), 6.94 (d, 1H, J=8 Hz), 5.62 (s, 2H), 2.64 (s, 3H)2.36˜2.14 (m, 1H), 1.40˜0.90(m, 4H) ##STR96## NMR (90 MHz, CDCl₃, δvalue): 8.16 (d, 1H, J=8 Hz), 7.80˜7.06 (m, 8H), 6.98 (d,1H,J=8Hz),5.56(s,2H),3.44˜2.90(m, 1H), 2.70 (s, 3H), 2.40˜1.40 (m, 8H)##STR97## NMR (90 MHz, CDCl₃, δ value): 8.22 (d, 1H, J=8 Hz), 7.80˜7.12(m, 8H), 7.03 (d, 1H, J=8 Hz), 5.54 (s, 2H), 3.08 (t, 2H, J=6 Hz),2.89(q,2H, J=6 Hz),2.10˜1.70(m,2H), 1.38 (t, 3H, J=6 Hz), 1.06 (t, 3H,J=6 Hz) ##STR98## NMR (90 MHz, CDCl₃, δ value): 8.18(d, 1H,J=8 Hz),7.80˜6.94 (m,9H),5.48 (s, 2H), 3.80˜3.40 (m, 1H), 2.74 (s, 3H), 2.66˜1.88(m,6H) ##STR99## NMR (90 MHz, CDCl₃, δ value): 8.18 (d, 1H, J=5Hz), 7.80˜7.10 (m, 8H), 7.01 (d, 1H, J=5 Hz), 5.57 (s, 2H), 3.10˜2.80(m, 1H), 2.72 (s, 3H), 2.04˜1.60 (m, 2H), 1.34 (d, 3H, J=6 Hz), 0.84 (t,3H, J=6 Hz) ##STR100##

NMR (90 MHz, CDCl₃, δ value): 8.18 (d, 1H, J=8 Hz), 7.80˜7.10 (m, 8H),7.02 (d, 1H, J=8 Hz), 5.56 (s, 2H), 2.76 (d, 2H, J=6 Hz), 2.40˜1.08 (m,1H), 1.00 (d, 6H) ##STR101## NMR (90 MHz, CDCl₃, δ value): 8.20 (d, 1H,J=5 Hz), 7.84˜6.90 (m, 9H), 5.57 (s, 2H), 3.40˜3.00 (m, 1H), 2.70 (m,3H), 1.37 (s,6H,J=7 Hz) ##STR102## NMR (90 MHz, CDCl₃, δ value): 8.38(d, 1H, J=2Hz), 8.13 (d, 1H, J=2Hz), 7.82 ˜7.10 (m, 8H), 5.51 (s, 2H),2.87 (q, 2H, J=7 Hz), 1.41 (t,3H,J=7 Hz) ##STR103## NMR (90 MHz, CDCl₃,δ value): 8.18 (d, 1H, J=6 Hz), 7.80˜7.08 (m, 8H), 6.68 (d, 1H,J=6Hz),5.52(s,2H),4.10(s,3H),2.80 (t, 2H, J=6 Hz), 2.10˜1.64 (m, 2H), 1.01(t, 3H,J=6 Hz) ##STR104## NMR (90 MHz, CDCl₃, δ value): 8.28 (d, 1H, J=6Hz), 7.80˜7.20 (m, 8H), 7.06 (d, 1H, J=6 Hz), 5.68 (s, 2H), 4.69 (s,2H), 3.40 (s,3H),2.72(s,3H) ##STR105## NMR (90 MHz, CDCl₃, δ value):8.17 (d, 1H, J=8 Hz), 7.84˜7.28 (m,8H), 7.00 (d, 1H, J=8 Hz), 6.16 (q,1H, J=8 Hz), 2.80 (t, 2H, J=6 Hz),2.69(s,3H),2.17 (d,3H,J=8 Hz),2.00˜1.60 (m, 2H), 0.98 (t, 3H. J=6 Hz) ##STR106## NMR (90 MHz, CDCl₃, δvalue): 8.15 (d, 1H, J=5 Hz), 7.74 (dd, 1H, J=8 Hz, 1Hz), 7.61 (td, 1H,J=8 Hz, 1Hz), 7.51˜7.39 (m, 6H), 6.99(d, 1H, J=8Hz),5.46(s,2H),3.40(q,2H,J=7 Hz), 2.65 (s, 3H), 1.45 (t, 3H, J=7 Hz)##STR107## NMR (90 MHz, CDCl₃, δ value): 8.15 (d, 1H, J=8 Hz), 7.74 (d,1H, J=8 Hz), 7.61 (td, 1H, J=8 Hz, 1Hz), 7.51˜7.39 (m, 8H), 7.00 (d, 1H,J=8 Hz), 5.46 (s, 2H), 2.80(s, 3H), 2.65 (s,3H) ##STR108## NMR(90 MHz,CDCl₃, δ value): 7.96 (d, 1H, J=8 Hz), 7.80˜7.07 (m, 9H), 5.51 (s, 2H),2.83 (q, 2H, J=8 Hz), 1.40 (t, 3H, J=8 Hz) ##STR109## NMR (90 MHz,CDCl₃, δ value): 8.20(d, 1H,J=5 Hz), 7.72˜7.05(m, 7H), 7.03 (d, 1H, J=8Hz), 5.55 (s, 2H), 2.83 (t, 2H, J=7 Hz), 2.69 (s, 3H), 2.02˜1.60 (m,2H), 1.00 (t, 3H, J=7 Hz) ##STR110## NMR (90 MHz, CDCl₃, δ value): 8.17(d, 1H, J=1 Hz), 7.85˜7.05 (m, 9H), 5.53 (s,2H), 2.81 (t, 2H, J=7 Hz),2.47 (s, 3H), 2.08 ˜1.61 (m,2H), 1.01 (t,3H,J=7 Hz) ##STR111## NMR (90MHz, CDCl₃, δ value): 8.26(s, 1H), 7.78˜7.05(m,9H),5.51 (s,2H), 2.83 (t,2H, J=7 Hz), 2.71 (s, 3H), 2.03˜1.57 (m, 2H),1.00(t,3H,J=7 Hz)##STR112## NMR (400 MHz, CDCl₃, δ value): 7.75 (1H, dd, J=8 Hz, 1 Hz),7.63 (1H, td, J=8 Hz, 1Hz), 7.49 (2H, d, J=8 Hz), 7.46 (1H, dd, J=8 Hz,1 Hz), 7.43 (1H, td, J=8 Hz, 1 Hz), 7.30(2H, d, J=8 Hz), 6.88 (1H, s),5.64 (2H, s), 2.59(6H, s), 1.93˜1.86(1H, m), 1.19˜1.15 (2H, m),1.03˜0.98 (2H, m) ##STR113## NMR (400 MHz, CDCl₃, δ value): 9.20(1H, s),9.06(1H, s), 8.17 (1H, s), 7.76 (1H, dd, J=8 Hz, 1 Hz), 7.64 (1H, td,J=8 Hz, 1 Hz), 7.56 (2H, d, J=8Hz), 7.48˜7.43 (4H, m), 5.54 (2H, s)##STR114## NMR (400 MHz, CDCl₃, δ value): 9.09 (1H, s), 8.97 (1H, s),7.75 (1H, d, J=8 Hz), 7.63 (1H, td, J=8 Hz, 1 Hz), 7.52 (2H, d, J=8 Hz),7.45 (1H, d, J=8 Hz), 7.44 (1H, td, J=8 Hz, 1 Hz), 7.28 (2H, d, J=8 Hz),5.52 (2H, s), 2.85 (2H, t, J=8 Hz), 1.94˜1.85 (2H, m), 1.03 (3H, t, J=8Hz) ##STR115## NMR(400 MHz, CDCl₃, δ value): 7.75 (1H, dd, J=8 Hz, 1Hz),7.62 (1H, td, J=8 Hz, 1 Hz), 7.49˜7.41 (4H, m), 7.23 (2H, d, J=8 Hz),6.91 (1H, s), 5.54 (2H, s), 2.78 (2H, t, J=8 Hz), 2.64 (3H, s), 2.60(3H, s), 1.82˜1.73 (2H, m), 0.98 (3H, t, J=8 Hz)

PREPARATION EXAMPLE 17

(1) 4-Chloro-2,3-diaminopyridine ##STR116##

3.6 g of 2-amino-4-chloro-3-nitropyridine was added to 21 ml of methanoland24 ml of concentrated hydrochloric acid, and the mixture wasvigorously stirred. Powdery iron was added in small portions to themixture. 10 min after the completion of the addition, the mixture waspoured into an iced concentrated aqueous ammonia and extracted withethyl acetate. The extract was dried over magnesium sulfate, and thesolvent was distilled off in vacuo. The residue was purified by silicagel chromatography (CH₂ Cl₂ : MeOH=20:1-10:1) to prepare 2.6 g of4-chloro-2,3-diaminopyridine as a purplish white crystal.

NMR (90 MHz, CDCl₃, δ value): 7.20 (d, 1H, J=5 Hz), 8.48 (d, 1H, J=5Hz), 5.74 (bs, 2H), 4.87 (bs, 2H)

(2) 7-Chloro-2-n-propyl-3H-imidazo[4,5-b]pyridine ##STR117##

500 mg of 4-chloro-2,3-diaminopyridine was dissolved in THF, and 860 mgof dicyclohexylcarbodiimide, 570 mg of N-hydroxybenzotriazole and 0.4 mlof n-butyric acid were successively added thereto. The mixture wasstirred overnight at room temperature, and the solid was removed byfiltration. The solid was thoroughly washed with ethyl acetate. Themother liquor and wash liquid were collected, and the solvent wasdistilled off in vacuo. The residue was purified by silica gelchromatography (CH₂ Cl₂ : MeOH=40:1). The solid obtained by distillingoff the solvent in vacuo was heated to 140° C. The temperature of thesolid was returned to room temperature after 30 min, and the solid waspurified by column chromatography (Ch₂ Cl₂ : MeOH=20:1) to prepare 200mg of 7-chloro-2-n-propyl-3H-imidazo[4,5-b]pyridine containing someimpurities.

(3)7-Chloro-2-n-propyl-3-[(2'-methoxycarbonylbiphenyl-4-yl)methyl]-3H-imidazo[4,5-b]pyridine##STR118##

200 mg of the above-prepared7-chloro-2-n-propyl-3H-imidazo[4,5-b]pyridine and 380 mg of methyl2-(4-bromomethylphenyl)benzoate were dissolved in dimethylformamide, and50 mg of sodium hydride was added to the solution. The mixture wasstirred at room temperature for 20 min, and water was added thereto,followed by extraction with ethyl acetate. The extract was dried overmagnesium sulfate, and the solvent was distilled off in vacuo. Theresidue was purified by silica gel chromatography (benzene:ethylacetate=40:1+20:1) to prepare the intended product as a colorlessoleaginous substance. The yield was 140 mg.

NMR(90 MHz, CDCl₃, δ value): 8.23 (d, 1H, J=8 Hz), 7.82 (dd, 1H, J=8 Hz,1Hz), 7.51 (td, 1H,J=8 Hz, 1Hz), 7.40(td, 1H,J=8 Hz, 1Hz), 7.30(dd,1H,J=8 Hz, 1Hz), 7.27˜7.23 (m, 3H), 7.16 (d, 2H, J=8 Hz), 5.53 (s, 2H),3.61 (s, 3H), 2.85 (t, 2H, J=8 Hz), 1.88˜1.78 (m, 2H), 1.00(t,3H,J=8 Hz)

PREPARATION EXAMPLE 18

(1) 2-Mercapto-7-methyl-3H-imidazo[4,5-b]pyridine ##STR119##

5 g of potassium hydroxide dissolved in 30 ml of ethanol was dropwiseadded at 20° C. or below to a solution of 15 g of2,3-diamino-4-methylpyridine in 15 ml of carbon disulfide and 60 ml ofmethanol, and the mixture was refluxed for 2 hr. Water and 7 ml ofconcentrated hydrochloric acid were added thereto, and acetic acid wasthen added thereto to weakly acidify the mixture. The precipitated solidwas recovered by filtration. The solid was washed twice with a smallamount of methanol and then dried to prepare 12.3 g of2-mercapto-7-methyl-3H-imidazo-[ 4,5-b]pyridine as a clayish solid.

NMR (400 MHz, DMSO-d₆): 13.01 (bs, 1H9,12.83(bs, 1H), 7.95(d, 1H,J=5Hz), 6.94 (d, 1H, J=5 Hz), 2.36 (s, 3H)

(2) 7-Methyl-2-methylthio-3H-imidazo[4,5-b]pyridine ##STR120##

130 mg of sodium hydride was dropwise added at room temperature to asolution of 500 mg of 2-mercapto-7-methyl-3H-imidazo[4,5-b]pyridine indimethylformamide. The mixture was stirred for 10 min, and 0.21 ml ofiodomethane was added thereto, followed by reaction for 30 min. Waterwas added to the reaction mixture, and the mixture was extracted withethyl acetate. The extract was dried over magnesium sulfate, and thesolvent was distilled off in vacuo. The resultant solid was washed witha small amount of ethyl acetate to prepare 210 mg of7-methyl-2-methylthio-3H-imidazo[4,5-b]pyridine as a mud yellow solid.

(3) 7-methyl-2-methylthio-3-[(2'-methoxycarbonylbiphenyl-4-yl)methyl]-3H-imidazo[4,5-b]pyridine ##STR121##

200 mg of 7-methyl-2-methylthio-3H-imidazo[4,5-b]pyridine and 370 mg ofmethyl 2-(4-bromomethylphenyl)benzoate was dissolved indimethylformamide, and 48 mg of sodium hydride was added at roomtemperature to the solution under stirring. The reaction was allowed toproceed for 30 min. Water was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was dried overmagnesium sulfate, and the solvent was distilled off in vacuo. Theresidue was purified by silica gel chromatography (benzene:ethylacetate=10:1+3:2) to prepare the intended product as a colorlessoleaginous substance. The yield was 60 mg.

NMR(90 MHz, CDCl₃, δ value): 8.23 (d, 1H, J=5 Hz), 7.82 (dd,1H,J=8 Hz, 1Hz), 7.51 (td, 1H,J=8 Hz, 1Hz), 7.40 (td, 1H,J=8 Hz, 1Hz), 7.30 (dd, 1H,J=8 Hz, 1Hz), 7.27˜7.23 (m, 3H), 7.16 (d. 2H, J=8 Hz), 5.53 (s, 2H),3.61 (s, 3H), 2.85 (t, 2H, J=8 Hz), 1.88˜1.78 (m, 2H), 1.00(t,3H,J=8 Hz)

PREPARATION EXAMPLE 19

2-Cyclopropyl-3-{(2'-methoxycarbonylbiphenyl-4-yl)methyl}-7-methyl-3H-imidazo[4,5-b]pyridine##STR122##

1.64 g of 2-cyclopropyl-7-methyl-3H-imidazo[4,5-b]pyridine dissolved in30 ml of dimethylformamide was dropwise added to 400 mg of sodiumhydride. The mixture was stirred at room temperature for 30 min, and 3.1g of methyl-2-(4-bromomethylphenyl)benzoate dissolved in 20 ml ofdimethylformamide was dropwise added thereto. The mixture was stirredfor 10 min and then cooled, and an aqueous ammonium chloride solutionwas added thereto. The mixture was extracted with ethyl acetate. Theextract was washed thrice with water, dried over anhydrous magnesiumsulfate and then concentrated. The residue was subjected to columnchromatography (chloroform: ethanol=99:1). The first eluted isomer wasthe title compound (yield: 1.32 g).

NMR (90 MHz, CDCl₃, δ value): 8.16 (d, 1H, J=5 Hz), 7.85˜7.63 (m, 1H),7.56 ˜7.10 (m, 1H), 7.22 (s, 4H), 6.98 (d, 1H, J=8 Hz), 5.62 (s, 2H),3.60 (s, 3H), 2.64 (s, 3H), 2.10˜1.80 (m, 1H), 1.30˜0.82 (m, 4H)

2-hydroxymethyl-3-[(2'-methoxycarbonylbiphenyl-4-yl)methyl]-7-methyl-3H-imidazo[4,5-b]pyridine

50 ml (50 mmol) of a dichloromethane solution of 1M boron tribromide wasadded little by little dropwise to 100 ml of a dichloromethane solutionof 3.3 g (8.2 mmol) of 3-[(2'-methoxycarbonyl-biphenyl-4-yl)methyl]-2-methoxymethyl-7-methyl-3H-imidazo[4,5-b]pyridine, whilestirred and cooled with ice. The mixture was further stirred at a roomtemperature for 12 hours. Methanol was added dropwise to the productmixture, while stirred and cooled with ice, and the solvent wasdistilled out at a reduced pressure. The residue was mixed with waterand neutralized with sodium bicarbonate. It was weakly acidified withacetic acid and decanted to remove the water. Methanol was added to theresidue and distilled out at a reduced pressure. It was re-crystallizedfrom ethanol-isopropylether to obtain 2.4 g of the intended compound.

PREPARATION EXAMPLE 20

The following compounds were prepared according to the process describedin Preparation Examples 17 to 19. ##STR123## NMR(90 MHz, CDCl₃, δvalue): 7.80˜6.85 (m, 12H), 5.42 (s, 2H), 3.58 (s, 3H), 2.79(t, 2H, J=7Hz), 1.85˜1.00 (m, 4H), 0.86 (t,3H,J=7 Hz) ##STR124##

NMR (90 MHz, CDCl₃, δ value 8.21 (d, 1H, J=5 Hz), 7.90˜7.72 (m, 1H),7.58˜6.94 (s, 8H), 5.52 (s, 2H), 3.59 (s, 3H), 2.87 (q, 2H, J=8 Hz),2.69 (s, 3H), 1.35 (t, 3H, J=8 Hz) ##STR125##

NMR (90 MHz, CDCl₃, δ value): 8.20 (d, 1H, J=5 Hz), 7.93˜7.74 (m, 1H),7.55˜6.90 (m, 8H), 5.53 (s, 2H), 3.59 (s, 3H), 2.83 (t, 2H, J=7 Hz),2.69 (s, 3H), 1.95˜1.56 (m, 2H), 1.00 (t, 3H, J=7 Hz) ##STR126##

NMR (90 MHz, CDCl₃, δ value): 8.20 (d, 1H, J=5 Hz), 7.86˜7.68 (m, 1H),7.57˜6.92 (m, 8H), 5.52 (s, 2H), 3.60 (s, 3H), 2.85 (t, 2H, J=7 Hz),2.69 (s, 3H), 1.96˜1.14 (m, 4H), 0.91 (t, 3H, J=7 Hz) ##STR127##

NMR (400 MHz, CDCl₃, δ value): 8.21 (d, 1H, J=5 Hz), 7.80 (d, 1H, J=8Hz), 7.50 (t, 1H, J=8 Hz), 7.39 (t, 1H, J=8 Hz), 7.29 (d, 1H, J=8 Hz),7.23 (d, 2H, J=8 Hz), 7.14 (d, 2H, J=8 Hz), 7.03 (d, 1H, J=5 Hz), 5.56(s, 2H), 3.58 (s, 3H), 3.24˜3.13 (m, 1H), 2.71 (s, 3H), 1.36 (d, 6H, J=7Hz) ##STR128##

NMR (400 MHz, CDCl₃, δ value): 8.22 (d, 1H, J=5 Hz), 7.81 (d, 1H, J=8Hz), 7.50 (t, 1H, J=8 Hz), 7.40 (t, 1H, J=8 Hz), 7.30 (d, 1H, J=8 Hz),7.24 (d, 2H, J=8 Hz), 7.18 (d, 2H, J=8 Hz), 7.04 (d, 1H, J=5 Hz), 5.51(s, 2H), 3.81 (s, 3H), 2.68 (s, 3H), 2.58 (s, 3H) ##STR129##

NMR (400 MHz, CDCl₃, δ value): 8.15 (d, 1H, J=5 Hz), 7.79 (d, 1H, J=8Hz), 7.49 (td, 1H, J=8 Hz, 1 Hz), 7.38 (td, 1H, J=8 Hz, 1 Hz), 7.35˜7.29(m, 3H), 7.23 (d, 1H, J=8 Hz), 6.99 (dd, 2H, J=5 Hz, 1 Hz), 5.44 (s,2H), 3.59 (s, 3H), 3.39 (q, 2H, J=8 Hz), 2.64 (s, 3H), 1.44 (t, 3H, J=8Hz) ##STR130##

NMR (400 MHz, CDCl₃, δ value): 8.28 (d, 1H, J=5 Hz), 8.00 (d, 1H, J=8Hz), 7.75 (td, 1H, J=8 Hz, 1 Hz), 7.46 (td, 1H, J=8 Hz, 1 Hz), 7.38 (d,1H, J=8 Hz), 7.31˜7.11 (m, 4H), 7.05 (d, 1H, J=5 Hz), 5.65 (s, 2H), 4.65(s, 2H), 3.60 (s, 3H), 3.38 (s, 3H), 2.71 (s, 3H) ##STR131##

NMR (CDCl₃) δ; 8.05 (1H, d, J=5 Hz), 7.79 (1H, dd; J=1.8 Hz), 7.49 (1H,dt, J=1.8 Hz), 7.38 (1H, dt, J=1.8 Hz), 7.36 (2H, d, J=8 Hz), 7.30 (1H,dt, J=1.8 Hz), 7.23 (2H, d, J=8 Hz), 6.92 (1H, d, J=5 Hz), 5.30 (2H, s),4.64 (2H, q, J=7 Hz), 3.61 (3H, s), 2.56 (3H, s), 1.47 (2H, t, J=7 Hz)##STR132##

NMR (CDCl₃) δ: 8.06 (1H, d, J=5 Hz), 7.79 (1H, dd, J=1.8 Hz), 7.49 (1H,dt, J=1.8 Hz), 7.38 (1H, dt, J=1.8 Hz), 7.37 (2H, d, J=8 Hz, 7.29 (1H,dd, J=1.8 Hz), 7.23 (2H, d, J=8 Hz), 6.93 (1H, d, J=5 Hz), 5.30 (2H,s),4.54 (2H, t,J=7 Hz), 3.60 (3H,s), 2.56 (3H, s), 1.91˜1.82 (2H, m), 1.02(3H, t, J=7 Hz) ##STR133##

NMR(CDCl₃) δ: 7.79 (1H, dd, J=1.8 Hz), 7.49 (1H, dt, J=1.8 Hz), 7.38(1H, dt, J=1.8 Hz), 7.35 (2H, d, J=8 Hz), 7.31 (1H, dd, J=1.8 Hz), 7.22(2H, d, J=8 Hz), 6.79 (1H,s), 5.27 (2H, s), 4.60 (2H, q, J=7 Hz), 3.60(3H, s), 2.55 (3H, s), 2.51 (3H, s), 1.44 (3H, t, J=7 Hz) ##STR134##

NMR (CDCl₃) δ: 7.80 (1H, dd, J=1.8 Hz), 7.50 (1H, dt, J=1.8 Hz), 7.39(1H, dt, J=1.8 Hz), 7.32 (1H, dd, J=1.8 Hz), 7.25 (2H, d, J=8 Hz), 7.17(2H, d, J=8 Hz), 6.57 (1H, s), 5.32 (2H, s), 3.59 (3H, s), 3.55 (3H, s),2.48 (3H, s), 2.27 (3H, s), ##STR135##

NMR(CDCl₃) δ: 7.79 (1H, dd, J=1.8 Hz), 7.49 (1H, dt, J=1.8 Hz), 7.38(1H, dt, J=1.8 Hz), 7.35 (2H, d, J=8 Hz), 7.30 (1H, dd, J=1.8 Hz), 7.22(2H, d, J=8 Hz), 6.79 (1H, s), 5.28 (2H, s), 4.49 (2H, t, J=7 Hz), 3.60(3H, s), 2.56 (3H, s), 2.51 (3H, s), 1.88˜1.78 (2H, m), 0.99 (3H, t, J=7Hz) ##STR136##

NMR (400 MHz, DMSO-d₆, δ value): 8.23 (1H, d, J=5 Hz), 7.73 (1H, dd, J=8Hz, 1 Hz), 7.61 (1H, td, J=8 Hz, 1 Hz), 7.48 (1H, td, J=8 Hz, 1 Hz),7.40 (1H, dd, J=8 Hz, 1 Hz), 7.28 (2H, d, J=8 Hz), 7.24 (2H, d, J=8 Hz),7.14 (1H, d, J=5 Hz), 5.64 (2H, s), 4.73 (2H, s), 3.56 (3H, s), 2.59(3H, s) ##STR137##

NMR (400 MHz, CDCl₃, δ value): 9.08 (1H, s), 8.97 (1H, s), 7.84 (1H, dd,J=8 Hz, 1 Hz), 7.53 (1H, td, J=8 Hz, 1 Hz), 7.42 (1H, td, J=8 Hz, 1 Hz),7.31 (1H, dd, J=8 Hz, 1 Hz), 7.28 (2H, d, J=8 Hz), 7.20 (2H, d, J=8 Hz),5.50 (2H, 3.61 (3H, s), 2.86 (2H, t, J=8 Hz), 1.95˜1.85 (2H, 1.04 (3H,t, J=8 Hz) ##STR138##

NMR (400 MHz, CDCl₃, δ value): 7.80 (1H, dd, J=8 Hz, 1 Hz), 7.51 (1H,td, J=8 Hz, 1 Hz), 7.39 (1H, td, J=8 Hz, 1 Hz), 7.31 (1H, dd, J=8 Hz, 1Hz), 7.23 (2H, d, J=8 Hz), 7.15 (2H, d, J=8 Hz), 6.90 (1H, s), 5.51 (2H,s), 3.59 (3H, s), 2.77 (2H, t, J=8 Hz), 2.64 (3H, s), 2.60 (3H, s),1.81˜1.72 (2H, m), 0.98 (3H, t, J=8 Hz) ##STR139##

NMR (400 MHz, CDCl₃, δ value) 7.80 (1H, dd, J=8 Hz, 1 Hz), 7.50 (1H, td,J=8 Hz, 1 Hz), 7.39 (1H, td, J=8 Hz, 1 Hz), 7.31 (1H, dd, J=8 Hz, 1 Hz),7.24 (2H, d, J=8 Hz), 7.21 (2H, d, J=8 Hz), 6.87 (1H, s), 5.60 (2H, s),3.60 (3H, s), 2.58 (6H, s), 1.94˜1.87 (1H, m), 1.19˜1.15 (2H, m),1.02˜0.97 (2H, m)

EXAMPLE 1

2-n-Butyl-1-[{5'-chloro-2'-(1H-tetrazol-5-yl)-biphenyl-4-yl}methyl]benzimidazole##STR140##

1.2 g of2-n-butyl-1-{(5'-chloro-2'-cyanobiphenyl-4-yl)methyl}benzimidazoleprepared in Preparation Example 8, 910 mg of sodium azide and 750 mg ofammonium chloride were heated while stirring in 50 ml ofdimethylformamide as a reaction solvent at an internal temperature of125° C. for 50 hr. After cooling, a dilute sodium hydroxide solution andethyl acetate were added thereto for phase separation, thereby obtaininga watery phase. The watery phase was weakly acidified with acetic acid,extracted with chloroform and washed with water. The extract was driedover anhydrous magnesium sulfate, and the residue was subjected tosilica gel chromatography (chloroform:ethanol:acetic acid=98:2:0.2). Afraciton of the intended title compound was concentrated and thenrecrystallized from ethyl acetate-isopropyl ethermethanol. The yield was450 mg.

m.p. (° C.): 152˜155

NMR (90 MHz, CDCl₃, δ value ): 7.70˜7.00 (m, 7H), 7.06 (s, 4H), 5.50 (s,2H), 2.82 (t, 2H, J=7 Hz), 1.90˜1.00 (m, 4H), 0.87 (t, 3H, J=7 Hz)

EXAMPLE 2

2-Ethyl-7-methyl-3-[{2'-(1H-tetrazol-5-yl)-biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridine##STR141##

10 g (0.027M) of3-[(2'-cyanobiphenyl-4-yl)-methyl]-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine,5.3 g (0.081M) of sodium azide and 5.6 g (0.041M) of triethylaminehydrochloride were suspended in 70 ml of N-methylpyrrolidone. Thetemperature of an oil bath was raised to 150° to 160° C. over a periodof 20 min while stirring with a stirrer. The temperature was returned toroom temperature after 6 hr, and water was added thereto, The mixturewas washed with ethyl acetate (50 ml×3). The watery phase was acidifiedwith acetic acid and extracted with ethyl acetate (100 ml×5). Theextract was dried over magnesium sulfate, and the solvent was distilledoff in vacuo. The blackish brown oleaginous substance as the residue waspurified by medium pressure column chromatography (SiO₂,ACOEt:EtOH=40:1÷2.0:1÷10:1). The yield was 11 g. Brown oleaginoussubstance.

This oleaginous substance was dissolved in ethyl acetate, and activatedcarbon was added thereto. The mixture was stirred at 50° C. for 15 minand then subjected to spontaneous filtration (no significant decoloringcould be attained). The solvent was distilled off in vacuo, and theproduct was crystallized from hexanedichloromethane. The yield was 4.9g. The product was a white crystal.

NMR (90 MHz, DMSO--d₆, δ value): 8.19 (d, 1H, J=5 Hz), 7.89˜7.41 (m,4H), 7.23˜6.91 (m, 5H), 5.53 (m, 2H); 2.86 (q, 2H, J=6 Hz), 2.59 (m,3H), 1.18 (t, 3H, J=6 Hz)

EXAMPLE 3

7-Methyl-2-n-propyl-3-[{2'-(1H-tetrazol-5-yl)-biphenyl-4-yl}methyl]- 3H-imidazo[4,5-b]pyridine ##STR142##

5.3 g of3-[(2'-cyanobiphenyl-4-yl)methyl]-7-methyl-2-n-propyl-3H-imidazo[4,5-b]pyridine,5.85 g of sodium azide and 6.19 g of triethylamine hydrochloride wereheated in 120 ml of N-methylpyrrolidone as a reaction solvent at aninternal temperature of 138° C. for 8 hr under stirring. After cooling,a dilute aqueous sodium hydroxide solution and ethyl acetate were addedthereto to cause phase separation, thus obtaining a watery phase. Thewatery phase was weakly acidified with acetic acid and extracted thricewith ethyl acetate, and the extract was washed four times with water.Methanol was added to the washed extract to dissolve the precipitatedcrystal in the organic phase, and the organic phase was dried overanhydrous magnesium sulfate. The dried organic phase was concentrated,and the residue was subjected to silica gel chromatography (chloroform:ethanol : acetic acid=97:3:0.2). A fraction of the intended titlecompound was concentrated and recrystallized from ethanol. The yield was4.6 g. The melting point was 200° to 202° C.

NMR (90 MHz, DMSO--d₆, δ value): 8.14 (d, 1H, J=5 Hz), 7.87˜7.32 (m,4H), 7.18˜6.92 (m, 5H), 5.49 (s, 1H), 2.78 (t, 2H, J=7 Hz), 2.55 (s,3H), 1.94˜1.43 (m, 2H), 0.92 (t, 3H, J=7 Hz)

EXAMPLE 4

The following compounds were synthesized according to the processdescribed in Examples 1 to 3. The names, chemical structural formulaeand physical constants of the synthesized compounds will be describedbelow.

(1)2-n-Butyl-1-[{2'-methoxy-6'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]benzimidazole##STR143##

m.p. (° C.): 230.5˜233

NMR (90 MHz, DMSO--d₆, δ value): 7.65˜7.00 (m, 7H), 6.98 (s, 4H), 5.45(s, 2H), 3.71 (s, 3H), 2.78 (t, 2H, J=7 Hz), 1.85˜1.05 (m, 4H), 0.87 (t,3H, J=7 Hz)

(2)2-n-Pentyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-pyridine##STR144##

m.p. (° C.): 158˜161

NMR (90 MHz, DMSO--d₆, δ value): 8.29 (dd, 1H, J=5 Hz), 7.99 (dd, 1H,J=1 Hz, 8 Hz), 7.80˜7.35 (m, 4H), 7.24 (dd, 1H, J=5 Hz, 8 Hz), 7.06(s,4H), 5.51 (s,2H), 2.81 (t, 2H, J=8 Hz), 1.90˜1.00 (m, 6H), 0.83 (t,3H, J=7 Hz)

(3) 2-n-Butyl-1-[{4'-chloro-2'-(1H-tetrazol-5-yl )biphenyl,4-yl}methyl]benzimidazole ##STR145##

m.p. (° C.): 202˜204

NMR (90 MHz, DMSO--d₆, δ value): 7.78˜6.95 (m, 7H), 7.03 (s, 4H), 5.49(s, 2H), 2.82 (t, 2H, J=7 Hz), 1.90˜1.00 (m, 4H), 0.86 (t, 3H, J=7 Hz)

(4)2-n-Butyl-5-methoxy-1-[{2'-1H-tetrazol-5-yl)biphenyl-yl}methyl]benzimidazole##STR146##

NMR (90 MHz, DMSO--d₆, δ value): 7.79˜7.43 (m, 4H), 7.37 (d, 1H, J=9Hz), 7.14 (d, 1H, J=3 Hz), 7.07 (s, 4H), 6.81 (dd, 1H, J=9 Hz, 3 Hz),5.45 (s, 2H), 3.77 (s, 3H), 2.78 (t, 2H, J=6 Hz), 1.85˜1.10 (m, 4H),0.86 (t, 3H, J=6 Hz)

(5)2-n-Butyl-4-carbamoyl-1-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]benzimidazole##STR147##

NMR (90 MHz, DMSO--d₆, δ value ): 7.95˜6.84 (m, 11H), 5.53 (s, 2H), 2.90(t, 2H, J=6 Hz), 1.93˜1.13 (m, 4H), 0.87 (t, 3H, J=6 Hz)

(6)2-n-Butyl-5-hydroxy-1-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]benzimidazole##STR148##

NMR (90 MHz, DMSO--d₆, δ value): 7.79˜6.76 g(m, 10H), 6.67 (dd, 1H, J=9Hz, 3 Hz), 5.39 (s, 2H), 2.77 (t, 2H, J=6 Hz), 1.87˜1.11 (m, 4H), 0.86(t, 3H, J=6 Hz)

(7)2-n-Butyl-3-[{2'-(1H-tetrazol-5-yl)-biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridine##STR149##

NMR (90 MHz, DMSO--d₆, δ value ): 8.34 (dd, 1H, J=5 Hz, 1 Hz), 8.02 (dd,1H, J=8 Hz, 1 Hz), 7.81˜7.41 (m, 4H), 7.27 (dd, 1H, J=5 Hz, 8 Hz), 7.07(s, 4H), 5.55 (s, 2H), 2.82 (t, 2H, J=6 Hz), 1.00˜1.13 (m, 4H), 0.87 (t,3H, J=6 Hz)

(8) 2-n-Butyl-1-[{5'-methoxy-2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]benzimidazole ##STR150##

m.p. (° C.): 140˜143

NMR (90 MHz, DMSO--d₆, δ value): 7.66˜7.30 (m, 3H), 7.25˜6.80 (m, 8H),5.47 (s, 2H), 3.84 (s, 3H), 2.82 (t, 2H, J=7 Hz), 1.90˜1.05 (m, 4H),0.87 (t, 3H, J=7 Hz)

(9)3-[{5'-Chloro-2'-(1H-tetrazol-5-yl)-biphenyl-4-yl}methyl]-2-n-propyl-3H-imidazo[4,5-b]pyridine##STR151##

NMR (90 MHz, DMSO--d₆, δ value): 8.29 (dd, 1H, J=1 Hz, 5 Hz), 8.00 (dd,1H, J=1 Hz, 8 Hz), 7.75˜7.30 (m, 3H), 7.25 (dd, 1H, J=5 Hz, 8 Hz), 7.09(s, 4H), 5.52 (s, 2H), 2.79 (t, 2H, J=7 Hz), 1.95˜1.45 (m, 2H), 0.93 (t,3H, J=7 Hz)

(10)3-[{4'-Chloro-2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-2-n-propyl-3H-imidazo[4,5-b]pyridine##STR152##

m.p. (° C.): 180˜183

NMR (90 MHz, DMSO--d₆, δ value ): 8.29 (dd, 1H, J=1 Hz, 5 Hz), 7.99 (dd,1H, J=1 Hz, 8 Hz), 7.80˜7.37 (m, 3H), 7.25 (dd, 1H, J=5 Hz, 8 Hz), 7.06(s, 4H), 5.51 (s, 2H), 2.79 (t, 2H, J=7 Hz), 1.95˜1.42 (m, 2H), 0.92 (t,3H, J=7 Hz)

(11)2-n-Butyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazo[4,5-c]pyridineammonium salt ##STR153##

NMR (90 MHz, DMSO--d₆, δ value): 8.85 (s, 1H), 8.27 (d, 1H, J=5 Hz),7.75˜7.25 (m, 5H), 7.19˜6.84 (m, 4H), 5.50 (s, 2H), 2.86 (t, 2H, J=6Hz), 1.92˜1.08 (m, 4H), 0.85 (t, 3H, J=6 Hz)

(12) 2-n-Propyl-1-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-1H-imidazo[4,5-b]pyridine ##STR154##

NMR (90 MHz, DMSO--d₆, δ value): 8.31 (dd, 1H, J=1 Hz, 5 Hz), 7.88 (dd,1H, J=1 Hz, 8 Hz), 7.76˜7.32 (m, 2H), 7.16 (dd, 1H, J=5 Hz, 8 Hz), 7.06(s, 4H), 5.53 (s, 2H), 2.88 (t, 2H, J=6 Hz), 1.90˜1.16 (m, 2H), 0.92 (t,3H, J=6 Hz)

(13)2,7-Dimethyl-3[{2'-(1H-tetrazol-5-yl)-biphenyl-4-yl}methyl]-3H-imidazo[4,5,b]pyridineammonium salt ##STR155##

NMR (90 MHz, DMSO--d₆, δ value): 8.12 (d, 1H, J=5 Hz), 7.64˜7.24 (m,4H), 7.10˜6.96 (m, 5H), 5.44 (s, 2H), 2.55 (s, 3H), 2.53 (s,3H)

(14)2-n-Butyl-7-methyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridineammonium salt ##STR156##

NMR (90 MHz, DMSO--d₆, δ value): 8.14 (d, 1H, J=5 Hz), 7.60˜7.20 (m,4H), 7.16˜6.80 (m, 5H), 5.46 (s, 2H), 2.84 (t, 2H, J=7 Hz), 2.60 (s, 2H,J=7 Hz), 1.84˜1.10 (m, 4H), 0.96 (t, 3H, J=6 Hz)

(15) 7-Methyl-2-phenyl-3[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl],3H-imidazo[4,5-b]pyridine ammonium salt ##STR157##

NMR (90 MHz, CDCl₃, δ value): 8.22 (d, 1H, J=5 Hz), 7.80˜7.30 (m, 9H),7.16 (d, 1H, J=5 Hz), 7.04˜6.80 (m, 4H), 5.56 (s, 2H), 2.65 (s, 3H)

(16)2-Cyclopropyl-7-methyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo-]4,5-b]pyridineammonium salt ##STR158##

NMR (90 MHz, DMSO--d₆, δ value ): 8.06 (d, 1H, J=5 Hz), 7.60˜7.16 (m,4H), 7.12˜6.88 (m, 5H), 5.54 (s. 2H), 2.50 (s, 3H), 2.40˜2.04 (m, 1H),1.08 (d, 4H, J=6 Hz)

(17)2-Cyclopentyl-7-methyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo-[4,5-b]pyridineammonium salt ##STR159##

NMR (90 MHz, DMSO--d₆, δ value): 8.08 (d, 1H, J=5 Hz), 7.70˜7.20 (m,4H), 7.10˜6.80 (m, 5H), 5.50 (s, 2H), 3.50˜3.04 (m, 1H), 2.56 (s, 3H),2.10˜1.40 (m, 8H)

(18) 2-Ethyl-7-n-propyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridine ammonium salt##STR160##

NMR (90 MHz, DMSO--d₆, δ value): 8.16 (d, 1H, J=5 Hz ), 7.68˜7.18 (m,4H), 7.10˜6.90 (m, 5H), 5.44 (s, 2H), 3.10˜2.60 (m, 4H), 2.0˜1.60 (m,2H), 1.18 (t, 3H, J=6 Hz), 0.96 (t, 3H, J=6 Hz)

(19)2-Cyclobutyl-7-methyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo-[4,5-b]pyridine ammonium salt ##STR161##

NMR (90MHz, DMSO--d₆, δ value): 8.14 (d; 1H, J=5 Hz), 7.64˜7.20 (m, 4H),7.16˜6.84 (s, 5H), 5.38 (s, 2H), 3.90˜3.60 (m, 1H), 2.60 (s, 3H),2.55˜1.80 (m, 6H)

(20) (±)7-Methyl-2-(1-methylpropyl)-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridineammonium salt ##STR162##

NMR (90 MHz, DMSO--d₆, δ value): 8.14 (d, 1H, J=5 Hz), 7.64˜7.24 (m,4H), 7.12˜6.86 (m, 5H), 5.50 (s, 2H), 3.22˜2.84 (m, 1H), 2.58 (s, 3H),1.96˜1.42 (m, 2H), 1.21 (d, 3H, J=6 Hz), 0.76 (t, 3H, J=6 Hz)

(21)(7-Methyl-2-(2-methylpropyl)-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridine ammonium salt ##STR163##

NMR (90 MHz, DMSO--d₆, δ value): 8.15 (d, 1H, J=5 Hz), 7.64˜7.26 (m,4H), 7.16˜6.86 (m, 5H), 5.48 (s, 2H), 2.74 (d, 2H, J=6 Hz), 2.60 (s,3H), 2.38˜2.00 (m, 1H), 3.96 (d, 6H)

(22)2,7-Diethyl-3-[{2'-(1H-tetrazol-5-yl)-biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]-pyridineammonium salt ##STR164##

NMR (90 MHz, DMSO--d₆, δ value): 8.18 (d, 1H, J=5 Hz), 7.62˜7.20 (m,4H), 7.14˜6.96 (m, 5H), 5.46 (s, 2H), 3.00 (q, 2H, J=6 Hz), 2.86 (q, 2H,J=6 Hz), 1.36 (t, 3H, J=6 Hz), 1.32 (t, 3H, J=6 Hz)

(23)2-n-Butyl-1-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]benzimidazole##STR165##

m.p. (° C.): 232˜235

NMR (90 MHz, DMSO--d₆, δ value): 7.80˜7.34 (m, 6H), 7.33˜6.95 (m, 2H),7.05 (s, 4H), 5.48 (s, 2H), 2.82 (t, 2H, J=7 Hz), 1.93˜1.08 (m, 4H),0.88 (t, 3H, J=7 Hz)

(24)2-n-Butyl-4-methyl-1-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}biphenyl-4-yl}methyl]benzimidazoleammonium salt ##STR166##

NMR (90 MHz, DMSO--d₆, δ value): 7.79˜7.41 (m, 4H), 7.39˜6.87 (m, 7H),5.50 (s, 2H), 2.82 (t, 2H, J=7 Hz), 2.54 (s, 3H), 1.86˜1.20 (m, 4H),0.88 (t, 3H, J=7 Hz)

(25)2-n-Butyl-5-fluoro-1-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]benzimidazole##STR167##

NMR (90 MHz, DMSO--d₆, δ value): 7.75˜7.27 (m, 6H), 7.19˜6.87 (m, 5H),5.49 (s, 2H), 2.81 (t, 2H, J=7 Hz), 1.85˜1.13 (m, 4H), 0.86 (t, 3H, J=7Hz)

(26)2-n-Butyl-5-fluoro-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]benzimidazole##STR168##

NMR (90MHz, DMSO--d₆, δ value): 7.57˜7.30 (m, 6H), 7.25˜6.87 (m, 5H),5.49 (s, 2H), 2.78 (t, 2H, J=7 Hz), 1.87˜1.11 (m, 4H), 0.84 (t, 3H, J=7Hz)

(27)2-N-Butyl-3-[{4'-chloro-2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo-[4,5-b]pyridine##STR169##

m.p. (° C.): 161˜163

NMR (90 MHz, DMSO--d₆, δ value): 8.28 (dd, 1H, J=1 Hz, 5 Hz), 7.99 (dd,1H, J=1 Hz, 8 Hz), 7.82˜7.35 (m, 3H), 7.24 (dd, 1H, J=5 Hz, 8Hz), 7.07(s, 4H), 5.51 (s, 2H), 2.81 (t, 2H, J=8 Hz), 1.90˜1.00 (m, 4H), 0.85 (t,3H, J=7 Hz)

(28)2-Ethyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridine##STR170##

m.p. (° C.): 142˜145

NMR (90 MHz, DMSO--d₆, δ value): 8.34 (dd, 1H, J=1 Hz, 5 Hz), 8.02 (dd,1H, J=1 Hz, 8 Hz), 7.75˜7.37 (m, 4H), 7.24 (dd, 1H, J=5 Hz, 8 Hz), 7.06(s, 4H), 5.50 (s, 2H), 2.83 (q, 2H, J=7 Hz), 1.25 (t, 3H, J=7 Hz)

(29)2-n-Butyl-3-[{5'-chloro-2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]-pyridine##STR171##

NMR (90 MHz, DMSO--d₆, δ value): 8.29 (dd, 1H, J=1 Hz, 5 Hz), 8.00 (dd,1H, J=1 Hz, 8 Hz), 7.75˜6.90 (m, 4H), 7.09 (2,4H), 5.52 (s, 2H), 2.81(t, 2H, J=7 Hz), 1.90˜1.05 (m, 4H), 0.86 (t, 3H, J=7 Hz)

(30)2-n-Butyl-3-[{5'-methoxy-2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]-pyridine##STR172##

NMR (90 MHz, DMSO--d₆, δ value): 8.29 (dd, 1H, J=1 Hz, 5 Hz), 7.99 (dd,1H, J=1 Hz, 8 Hz), 7.57 (d, 1H, J=9 Hz), 7.33˜6.80 (m, 7H), 5.51 (s, 2H)3.85 (s, 3H) 2.82 (t, 2H, J=7 Hz), 1.90˜1.05 (m, 4H), 0.86 (t, 3H, J=7Hz)

(31)2-n-Butyl-3-[{4'-methoxy-2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]-pyridine##STR173##

NMR (90 MHz, DMSO--d₆, δ value ): 8.33 (dd, 1H, J=5 Hz, 1 Hz), 8.03 (dd,1H, J=8 Hz, 1 Hz), 7.59˜6.80 (m, 8H), 5.53 (s, 2H), 3.86 (s, 3H), 2.85(t, 2H, J=6 Hz), 1.93˜1.10 (ms 4H), 0.88 (t, 3H, J=6 Hz)

(32)2-n-Propyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridine##STR174##

m.p. (° C.): 226˜229.5

NMR (90 MHz, DMSO--d₆, δ value): 8.30 (dd, 1H, J=5 Hz), 8.01 (dd, 1H,J=8 Hz, 1 Hz), 7.82˜7.37 (m, 4H), 7.26 (dd, 1H, J=8 Hz, 1 Hz), 7.09 (s,3H), 5.54 (s, 2H), 2.79 (t, 2H, J=6 Hz), 1.95˜1.39 (m, 2H), 0.92 (t, 3H,J=6 Hz)

(33)2-n-Propyl-3-[{4'-methoxy-2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]benzimidazole##STR175##

NMR (90 MHz, DMSO--d₆, δ value ): 7.73˜7.03 (m, 7H), 7.00 (s, 4H), 5.46(s, 2H), 3.83 (s, 3H), 2.82 (t, 2H, J=6 Hz), 1.88˜1.12 (m, 4H), 0.86 (t,3H, J=6 Hz)

(34) 2-n-Butyl-1-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]benzimidazo[4,5-c]pyridine ammonium salt ##STR176##

NMR (90 MHz, DMSO--d₆, δ value): 8.84 (s, 1H), 8.21 (d, 1H, J=5 Hz),7.79˜7.34 (m, 5H), 7.07 (s, 4H), 5.57 (s, 2H), 2.88 (t, 2H, J=6 Hz),1.92˜1.08 (m, 4H), 0.84 (t, 3H, J=6 Hz)

(35)2-Isopropyl-7-methyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridineammonium salt ##STR177##

NMR (90 MHz, DMSO--d₆, δ value): 8.14 (d, 1H, J=5 Hz), 7.60˜6.80 (m,9H), 5.48 (s, 2H), 4.90 (bs, 4H), 3.42˜3.00 (m, 1H), 2.56 (s, 3H), 1.23(d, 6H, J=7 Hz)

(36)2-Bromo-2-ethyl-3-[{2'-(1H-tetrazol-5-yl)-biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridine##STR178##

NMR (90 MHz, DMSO--d₆, δvalue): 8.38 (d, 1H, J=2 Hz), 8.27 (d, 1H, J=2Hz), 7.70˜6.85 (m, 8H), 5.48 (s, 2H), 2.83 (q, 2H, J=7 Hz), 1.24 (t, 3H,J=7 Hz)

(37)5-Chloro-2-ethyl-7-methyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridine##STR179##

m.p. (° C.): 258 (dec)

NMR (90 MHz, DMSO--d₆, δ value): 8.07 (d, 1H, J=8 Hz), 7.70˜7.35 (m,4H), 7.31 (d, 1H, J=8 Hz), 7.07 (s, 4H), 5.46 (s, 2H), 2.81 (q, 2H, J=7Hz), 1.24 (t, 3H, J=7 Hz)

(38)3-[{5'-Chloro-2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-7-methyl-2-n-propyl-3H-imidazo[4,5-b]pyridine##STR180##

m.p. (° C.): 157˜159

NMR (90 MHz, DMSO--d₆, δ value): 8.14 (d, 1H, J=8 Hz), 7.75˜7.48 (m,3H), 7.08˜6.97 (m, 5H), 5.49 (s, 2H), 2.78 (t, 2H, J=7 Hz), 2.55 (s,3H), 1.92˜1.45 (m, 2H), 0.92 (t, 3H, J=7 Hz)

(39)6-Methyl-2-n-propyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridine##STR181##

m.p. (° C.): 144˜147

NMR (90 MHz, DMSO--d₆, δ value): 8.12 (d, 1H, J=1 Hz), 7.88˜7.26 (m,5H), 7.05 (s, 4H), 5.47 (s, 2H), 2.77 (t, 2H, J=7 Hz), 0.91 (t, 3H, J=7Hz)

(40)6-Chloro-7-methyl-2-n-propyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridine##STR182##

m.p. (° C.): 233-235

NMR (90 MHz, DMSO--d₆, δ value): 8.27 (s, 1H), 7.75˜7.30 (m, 4H), 7.05(s, 4H), 5.48 (s, 2H), 2.79 (t, 2H, J=7 Hz), 2.58 (s, 3H), 1.93˜1.45 (m,2H), 0.92 (t, 3H, J=7 Hz)

(41)7-Methoxy-2-n-propyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridine##STR183##

m.p. (° C.): 130˜135

NMR (90 MHz, DMSO--d₆, δ value ): 8.11 (d, 1H, J=5 Hz), 7.60˜6.88 (m,8H), 6.80 (d, 1H, J=5 Hz), 5.42 (s, 4H), 4.04 (s, 3H), 2.76 (t, 2H, J=7Hz), 1.96˜1.50 (m, 2H), 0.92 (t, 3H, J=7 Hz)

(42)2-Methoxymethyl-7-methyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo-[4,5-b]pyridine##STR184##

m.p. (° C.): 127˜135

NMR (90 MHz, DMSO--d₆, δ value): 8.18 (d, 1H, J=5 Hz), 7.60˜6.94 (m,9H), 5.48 (s, 2H), 4.64 (s, 2H), 3.29 (s, 3H), 2.60 (s, 3H)

(43)7-Methyl-2-n-propyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridineammonium salt ##STR185##

m.p. (° C.): 118˜130

NMR (90 MHz, DMSO--d₆, δ value): 8.10 (d, 1H, J=5 Hz), 7.68˜7.36 (m,4H), 7.32˜6.92 (m, 5H), 6.02 (q, 1H, J=5 Hz), 2.80 (t, 2H, J=6 Hz), 2.58(s, 3H), 2.08 (d, 3H, J=8 Hz), 1.96˜1.50 (m, 2H), 0.96 (t, 3H, J=6 Hz)

(44)2-Ethylthio-7-methyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo-[4,5-b]pyridineammonium salt ##STR186##

m.p. (° C.): 149˜159

NMR (400 MHz, CDCl₃ +DMSO--d₆, δ value): 8.08 (d, 1H, J=5 Hz), 7.68 (dd,1H, J=7 Hz, 1 Hz), 7.48 (td, 1H, J=8 Hz, 1 Hz), 7.44˜7.37 (m, 2H), 7.19(d, 2H, J=8 Hz), 7.09 (d, 2H, J=8 Hz), 6.99 (d, 1H, J=5 Hz), 4.97 (s,2H), 3.38 (q, 2H, J=7 Hz), 2.61 (s, 3H), 1.45 (t, 3H, J=7 Hz)

(45) 7-Methyl-2-methylthio-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo-[4,5-b]pyridine ammonium salt##STR187##

m.p. (° C.): 150˜175

NMR (400 MHz, CDCl₃ +DMSO--d₆, δ value): 8.10 (d, 1H, J=5 Hz), 7.66 (dd,1H, J=8 Hz, 1 Hz), 7.50˜7.36 (m, 3H), 7.19 (d, 2H, J=8 Hz), 7.14 (d, 2H,J=8 Hz), 7.00 (d, 1H, J=5 Hz), 5.36 (s, 2H), 2.79 (s, 3H), 2.62 (s, 3H)

(46) 2-Ethoxy-5,7-dimethyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridine ##STR188##

NMR (DMSO--d₆) δ: 7.66 (1H, dt, J=1.8 Hz), 7.65 (1H, d, J=8 Hz), 7.56(1H, dt, J=1.8 Hz), 7.52 (1H, d, J=8 Hz), 7.14 (2H, d, J=8 Hz), 7.04(2H, d, J=8 Hz), 6.86 (1H, s), 5.18 (2H, s), 4.53 (2H, q, J=7 Hz), 2.45(3H, s), 2.41 (3H, s), 1.34 (3H, t, J=7 Hz)

(47) 5,7-Dimethyl-2-methoxy-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridine ##STR189## (48)5,7-Dimethyl-2-n-propoxy-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4.5-b]pyridine ##STR190##

NMR (DMSO--d₆) δ: 7.66 (1H, dt, J=1.8 Hz), 7.65 (1H, d, J=8 Hz), 7.56(1H, dt, J=1.8 Hz), 7.51 (1H, d, J=8 Hz), 7.15 (2H, d, J=8 Hz), 7.05(2H, d, J=8 Hz), 6.86 (1H, s), 5.18 (2H, s), 4.43 (2H, t, J=7 Hz), 2.46(3H, s), 2.41 (3H, s), 1.78˜1.68 (2H, m), 0.90 (3H, t, J=7 Hz)

EXAMPLE 5

3- {2'-Carboxybiphenyl-4-yl)methyl}-2-cyclopropyl-7-methyl-3H-imidazo[4,5-b]pyridine ##STR191##

40 ml of ethanol and 20 ml of a 10% aqueous sodium hydroxide solutionwere added to 1.32 g of2-cyclopropyl-3-{2'-carboxybiphenyl-4-yl)methyl}-7-methyl-3H-imidazo[4,5-b]pyridine,and the mixture was heated under reflux for 21 hr. The reaction mixturewas concentrated to 30 ml, cooled and neutralized with 2N hydrochloricacid and acetic acid, and the precipitated crystal was collected byfiltration and recrystallized from water. The yield was 1.03 g.

m.p. (° C.): 221˜224

NMR (90 MHz, DMSO--d₆, δ value ): 8.12 (d, 1H, J=5 Hz), 8.75˜8.20 (m,4H), 7.26 (s, 4H), 7.04 (d, 1H, J=5 Hz), 5.63 (s, 2H), 2.50˜2.05 (m,1H), 1.24˜0.90 (m, 4H)

The following compounds were synthesized according to the processdescribed in Example 5. The names, chemical structure formulae andphysical constants of the synthesized compounds will be described below.

(1) 2-Butyl-1-{(2'-carboxylphenyl-4-yl)-methyl}benzimidazole ##STR192##

m.p. (° C.): 233˜235

NMR (90 MHz, DMSO--d₆, δ value): 7.75˜8.90 (m, 12H), 5.48 (s, 2H), 2.82(t, 2H, J=7 Hz) 1.95˜1.05 (m, 4H), 0.84 (t, 3H, J=7 Hz)

(2) 3-{(2'-Carboxybiphenyl-4-yl)methyl}-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine##STR193##

m.p. (° C.): 222˜224

NMR (90 MHz, DMSO--d₆, δ value ): 8.16 (d, 1H, J=5 Hz), 7.75˜6.96 (m,9H), 5.52 (s, 2H), 2.86 (q, 2H, J=7 Hz), 2.57 (s, 3H), 1.27 (t, 3H, J=7Hz)

(3)3-{(2'-Carboxybiphenyl-4-yl)methyl}-7-methyl-2-n-propyl-3H-imidazo[4,5-b]pyridine##STR194##

m.p. (° C.): 260˜263

NMR (90 MHz, DMSO--d₆, δ value ): 8.15 (d, 1H, J=5 Hz), 7.75˜6.95 (m,9H), 5.53 (s, 2H), 2.82 (t, 2H, J=7 Hz), 2.56 (s, 3H), 2.00˜1.48 (m,2H), 0.94 (t, 3H, J=7 Hz)

(4) 2-n-Butyl-3-{(2'-carboxybiphenyl-4-yl)-methyl}-7-methyl-3H-imidazo[4,5-b]pyridine##STR195##

m.p. (° C.): 230˜232

NMR (400 MHz, DMSO--d₆, δ value): 8.15 (d, 1H, J=5 Hz), 7.68 (d, 1H, J=8Hz), 7.52 (t, 1H, J=8 Hz), 7.41 (t, 1H, J=8 Hz), 7.30 (d, 1H, J=8 Hz),7.60 (d, 2H, J=8 Hz), 7.15 (d, 2H, J=8 Hz), 7.07 (d, 1H, J=5 Hz), 5.52(s, 2H), 2.83 (t, 2H, J=8 Hz), 2.54 (s, 3H), 1.72˜1.60 (m, 2H),1.40˜1.28 (m, 2H), 0.84 (t, 3H, J=8 Hz)

(5)3-{(2'-Carboxybiphenyl-4-yl)methyl}-2-isopropyl-7-methyl-3H-imidazo[4,5-b]pyridine##STR196##

m.p. (° C.): 241˜244

NMR (400 MHz, DMSO--d₆, δ value): 8.17 (d, 1H, J=5 Hz), 7.70 (d, 1H, J=8Hz), 7.54 (t, 1H, J=8 Hz), 7.43 (t, 1H, J=8 Hz), 7.33 (d, 1H, J=8 Hz),7.27 (d, 2H, J=8 Hz), 7.16 (d, 2H, J=8 Hz), 7.10 (d, 1H, J=5 Hz), 5.56(s,2H), 3.45˜3.20 (m, 1H), 2.58 (s, 4H), 1.25 (d, 6H, J=7 Hz)

(6) 3- {(2'-Carboxybiphenyl-4-yl)methyl}-2,7-dimethyl-3H-imidazo[4,5-b]pyridine ##STR197##

m.p. (° C.): 257˜259

NMR (400 MHz, DMSO--d₆, δ value): 8.16 (d, 1H, J=5 Hz), 7.70 (d, 1H, J=8Hz), 7.54 (t, 1H, J=8 Hz), 7.43 (t, 1H, J=8 Hz), 7.33 (d, 1H, J=8 Hz),7.28 (d, 2H, J=8 Hz), 7.20 (d, 2H, J=8 Hz), 7.08 (d, 1H, J=5 Hz), 5.52(s, 2H), 2.55 (s, 3H), 2.54 (s, 3H)

(7) 7-Methyl-2-(1-propenyl)-3-[(2'-carboxybiphenyl-4-yl)methyl]-3H-imidazo-[4,5-b]pyridine ##STR198##

NMR (400 MHz, DMSO--d₆, δ value): 8.14 (d, 1H, J=5 Hz), 7.67 (d, 1H, J=8Hz), 7.51 (td, 1H, J=8 Hz, 1 Hz), 7.40 (td, 1H, J=8 Hz, 1 Hz), 7.29 (d,1H, J=8 Hz), 7.27˜7.10 (m, 5H), 7.08 (d, 1H, J=5 Hz), 6.78 (d, 1H, J=15Hz), 5.59 (s, 2H), 2.56 (s, 3H), 1.96 (d, 3H, J=8 Hz)

(8) 7-Chloro-2-n-propyl-3-[(2'-carboxybiphenyl-4-yl)methyl]-3H-imidazo{4,5-b]pyridine ##STR199##

NMR (400 MHz, CDCl₃ ÷DMSO--d₆, δ value): 8.19 (d, 1H, J=5 Hz), 7.82 (d,1H, J=7 Hz), 7.44 (t, 1H, J=7 Hz), 7.34 (t, 1H, J=7 Hz), 7.29˜7.20 (m,4H), 7.11 (d,2H, J=8 Hz), 5.49 (s, 2H), 2.81 (t, 2H, J=8 Hz), 1.84˜1.73(m,2H), 0.96 (t, 3H, J=8 Hz)

(9)7-Methyl-2-methylthio-3-[(2'-carboxybiphenyl-4-yl)methyl]-3H-imidazo[4,5-b]pyridine##STR200##

NMR (400 MHz, CDCl₃ +DMSO--d₆, δ value): 8.13 (d, 1H, J=5 Hz), 7.80 (dd,1H, J=7 Hz, 1 Hz), 7.47 (td, 1H, J=7 Hz, 1 Hz), 7.39˜7.28 (m, 6H), 7.00(d, 1H, J=5 Hz), 5.41 (s, 2H), 2.79 (s, 3H), 2.64 (s, 3H)

(10) 7-Methoxymethyl-7-methyl-3-[(2'-carboxybiphenyl-4-yl)methyl]-3H-imidazo-[4,5-b]pyridine ##STR201##

NMR (400 MHz, DMSO--d₆, δ value): 8.23 (d, 1H, J=5 Hz), 7.67 (d, 1H, J=8Hz), 7.51 (td, 1H, J=8 Hz, 1 Hz), 7.40 (td, 1H, J=8 Hz, 1 Hz), 7.30 (d,1H, J=8 Hz), 7.26˜7.13 (m, 4H), 7.13 (d, 1H, J=5 Hz), 5.55 (s, 2H), 4.66(s, 2H), 2.26 (s, 3H), 2.56 (s, 3H)

(11)2-Cyclobutyl-7-methyl-3-[(2'-carboxybiphenyl-4-yl)methyl]-3H-imidazo[4,5-b]pyridine##STR202##

NMR (400 MHz, DMSO--d₆, δ value): 8.15 (d, 1H, J=5 Hz), 7.69 (d, 1H, J=8Hz), 7.52 (td, 1H, J=8 Hz, 1 Hz), 7.42 (td, 1H, J=8 Hz, 1 Hz), 7.31 (d,1H, J=8 Hz), 7.25 (d, 2H, J=8 Hz), 7.13 (d, 2H, J=8 Hz), 7.08 (d, 1H,J=5 Hz), 5.43 (s, 2H), 3.81 (quint, 1H, J=8 Hz), 2.58 (s, 3H), 2.45˜2.33(m, 2H), 2.25˜2.16 (m, 2H), 2.06˜1.93 (m, 1H), 1.90˜1.80 (m, 1H)

(12) 2-Ethylthio-7-methyl-3-[(2'-carboxybiphenyl-4-yl)methyl]-3H-imidazo[4,5-b]pyridine ##STR203##

NMR (400 MHz, CDCl₃ +DMSO--d₆, δ value): 8.11 (d, 1H, J=5 Hz), 7.02 (d,1H, J=8 Hz), 7.51 (td, 1H, J=8 Hz, 1 Hz), 7.41 (td, 1H, J=8 Hz, 1 Hz),7.34˜7.22 (m, 5H), 7.04 (d, 1H, J=5 Hz), 5.41 (s, 2H), 3.39 (q, 2H, J=8Hz), 2.58 (s, 3H), 1.44 (t, 1H, J=8 Hz)

(13)3-{(2'-Carboxybiphenyl-4-yl)methyl}-2-ethoxy-7-methyl-3H-imidazo[4,5-b]pyridine##STR204##

NMR (DMSO--d₆) δ: 8.00 (1H, d, J=5 Hz), 7.59 (1H, dd, J=1.8 Hz), 7.45(1H, dt, J=1.8 Hz), 7.36 (1H, dt, J=1.8 Hz), 7.30 (1H, d, J=8 Hz), 7.30(2H, d, J=8 Hz), 7.25 (2H, d, J=8 Hz), 7.00 (1H, d, J=5 Hz), 5.24 (2H,s), 4.60 (2H, q, J=7 Hz), 2.47 (3H, s), 1.41 (3H, t, J=7 Hz)

(14)3-{(2'-Carboxybiphenyl-4-yl)methyl}-2-methoxy-7-methyl-3H-imidazo[4,5-b]pyridine##STR205## (15)3-{(2'-Carboxybiphenyl-4-yl)methyl-2-n-propoxy-3H-imidazo[4,5-b]pyridine##STR206##

NMR (DMSO--d₆) δ: 8.01 (1H, d, J=5 Hz), 7.64 (1H, d, J=8 Hz), 7.49 (1H,t, J=8 Hz), 7.39 (1H, t, J=8 Hz), 7.30 (1H, d, J=8 Hz), 7.28 (4H, s),7.00 (1H, d, J=5 Hz), 5.25 (2H, s), 4.50 (2H, t, J=7 Hz), 2.47 (3H, s),1.83˜1.78 (2H, m), 0.96 (3H, t, J=7 Hz)

(16)3-{(2'-Carboxybiphenyl-4-yl)methyl}-5,7-dimethyl-2-ethoxy-3H-imidazo[4,5-b]pyridine##STR207##

NMR (CDCl₃) δ: 7.70 (1H, d, J=8 Hz), 7.54 (1H, t, J=8 Hz), 7.43 (1H, t,J=8 Hz), 7.33 (1H, d, J=8 Hz), 7.29 (2H, d, J=8 Hz), 7.24 (2H, d, J=8Hz), 6.87 (1H, s), 5.25 (2H, s), 4.56 (2H, q, J=7 Hz), 2.46 (3H, s),2.42 (3H, s), 1.38 (3H, t, J=7 Hz)

(17)3-{(2'-Carboxybiphenyl-4-yl)methyl}-5,7-dimethyl-2-methoxy-3H-imidazo[4,5-b]pyridine##STR208##

NMR (DMSO--d₆) δ: 7.70 (1H, d, J=8 Hz), 7.55 (1H, t, J=8 Hz), 7.44 (1H,t, J=8 Hz), 7.35 (1H, d, J=8 Hz), 7.29 (2H, d, J=8 Hz), 7.15 (2H, d, J=8Hz), 6.68 (1H, s), 5.28 (2H, s), 3.39 (3H, s), 2.40 (3H, s), 2.23 (3H,s)

(18)3-{(2'-Carboxybiphenyl-4-yl)methyl}-5,7-dimethyl-2-n-propoxy-3H-imidazo[4,5-b]pyridine##STR209##

NMR (DMSO--d₆) δ: 7.51 (1H, dd, J=1.8 Hz), 7.38 (1H, dt, J=1.8 Hz), 7.32(2H, t, J=8 Hz), 7.31 (1H, dt, J=1.8 Hz), 7.24 (1H, dd, J=1.8 Hz), 7.21(2H, d, J=8 Hz), 6.86 (1H, s), 5.21 (2H, s), 4.46 (2H, t, J=7 Hz), 2.47(3H, s), 2.42 (3H, s), 1.83˜1.73 (2H, m), 0.94 (3H, t, J=7 Hz)

EXAMPLE 6

2-Ethylsulfonyl-7-methyl-3[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazo[4.5-b]pyridine

6.4 g (15 mmol) of 2-ethylthio-7-methyl-3[(2'-(1H-tetrazol-5-yl)biphenyl -4-yl) methyl]-3H- imidazo[4.5-b]pyridine was dispersed in 150ml of dichloromethane. 150 ml of a dichloromethane solution of 3.94 g(23 mmol) of meta-chloro-perbenzoic acid was added dropwise to thesolution over 40 minutes, while agitated and cooled with water and ice.The mixture was stirred at room temperature for 20 minutes. The reactionproduct mixture was washed separately with 10% aqueous solution ofsodium bisulfate, a saturated aqueous solution of sodiuim bicarbonateand a saturated saline. The dichloromethane phase was separated andtaken, then dried with aqueous magnesium sulfate. The solvent wasdistilled out at a reduced pressure and the residue was treatedchromatographically with silicagel to obtain 5.93 g of the above namedcompound from the eluate of ethyl acetate and methanol (9:1 v/v).

EXAMPLE 7

2-Methoxy-7-methyl-3[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazo[4.5-b]pyridine

420 mg (2.2 mmol) of 28% methanol solution of sodium methoxide was addedto 10 ml of a methanol solution of 0.44 g (0.96 mmol) of2-ethylsulfonyl-7-methyl-3[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazo[4.5-b]-pyridine was dispersed in 150 ml of dichloromethane.The mixture was refluxed for 40 minutes. The solvent was distilled outat a reduced pressure. The residue was mixed with water and neutralizedwith 2N HCl. An extract with dichloromethane was washed with a saturatedsaline and dried with anhydrous magnesium sulfate. The solvent wasdistilled out at a reduced pressure. The residue was treated withethanol and ether for recrystallization to obtain 300 mg of the abovenamed compound.

EXAMPLE 7-1

2-Ethoxy-7-methyl-3[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazo[4,5-b]pyridinewas obtained in the same manner as shown in Example 7.

EXAMPLE 8

2-n-butoxy-7-methyl-3[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-3H-imidazo[4.5-b]pyridine

A mixture of 100 mg (1.3 mmol) of n-butanol, 400 mg (3.6 mmol) ofpotassium tert.-butoxide and DMF was heated at 80 degree C. for 5minutes. 300 mg (0.65 mmol) of2-ethyl-sulfonyl-7-methyl-3[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-3H-imidazo[4.5-b]pyridinewas added to the mixture. The resultant was heated for 2 hours. Thereaction product mixture was mixed with water, neutralized with 2n HCland extracted with dichloromethane. The dichloromethane phase was washedwith a saturated saline and dried with anhydrous magnesium sulfate. Thesolvent was distilled out at a reduced pressure and the residue wastreated with ether-hexane-dichloromethane or re-crystallization toobtained 140 mg of the intended compound.

The following compounds were produced by the same production process asshown above:

7-methyl-2-n-propoxy-3[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-3H-imidazo[4.5-b]pyridine

2-isopropoxy-7-methyl-3[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-3H-imidazo[4.5-b]pyridine

2-cyclopropylmethoxy-7-methyl-3[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-3H-imidazo[4.5-b]pyridine

EXAMPLE 9

7-methyl-3[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)-methyl]-1,3-dihydro-2-oxo-imidazo[4.5-b]pyridine

A mixture of 90 mg (0.23 mmol) of2-methoxy-7-methyl-3[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-3H-imidazo[4.5-b]pyridineand 1 ml of 48% HBr was stirred at a room temperature for 1.5 hours. Theproduct mixture was mixed with water to produce crystals, which wastaken out and washed with water to obtain 70 mg of the intendedcompound.

EXAMPLE 10

2-hydroxymethyl-7-methyl-3[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)-methyl]-3H-imidazo[4.5-b]pyridine

30 ml of a dichloromethane solution of 410 mg (1 mmol) of2-methoxy-methyl-7-methyl-3[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)-methyl]-3H-imidazo[4.5-b]pyridinewas stirred, cooled with ice. During this step, 10 ml (10 mmol) ofdichloromethane solution of 1M boron tribromide was added little bylittle thereto dropwise. The mixture was further agitated at a roomtemperature for 12 hours. The reaction product mixture was cooled, whilestirred. During this step, methanol was added little by little. Thesolvent was distilled out at a reduced pressure. The residue was mixedwith water, neutralized with sodium bicarbonate, adjusted to a weakacidity with acetic acid and decanted to remove the water. The residuewas mixed with methanol. The solvent was distilled out at a reducedpressure. The residue was treated with isopropylether forre-crystallization to obtain 330 mg of the intended compound.

EXAMPLE 11

2-chloroymethyl-7-methyl-3[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)-methyl]-3H-imidazo[4.5-b]pyridine

A mixture of 20 ml of dichloromethane and 2.2 g (5.5 mmol) of2-hydroxymethyl-7-methyl-3[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)-methyl]-3H-imidazo[4.5-b]pyridinewas stirred, cooled with ice. During this step, 1.6 ml of thionylchloride was added thereto. The mixture was further agitated at a roomtemperature for 1 hour. The solvent was distilled out at a reducedpressure. The residue was mixed with water, neutralized with sodiumbicarbonate, adjusted to a weak acidity with acetic acid and extractedwith dichloromethane. The dichloromethane phase was washed with asaturated saline and dried with anhydrous magnesium sulfate. The solventwas distilled out at a reduced pressure. The residue was treated withdichloromethane for re-crystallization to obtain 1.37 mg of the intendedcompound.

EXAMPLE 12

3-[(2'-carboxybiphenyl-4-yl)methyl]-2-hydroxy-methyl-7-methyl-3H-imidazo[4.5-b]pyridine

A mixture of 8 ml of an aqueous 10% sodium hydroxide solution of 500 mg(1.3 mmol) of2-hydroxymethyl-3-[(2'-methoxycarbonyl-biphenyl-4-yl)methyl]-7-methyl-3H-imidazo[4.5-b]pyridine and 20 ml of ethanol was heated for reflux for2 hours. The insoluble was removed out and the filtrate wasconcentrated. The residue was mixed with water and washed with ethylacetate. The aqueous phase was weakly acidified with 2N hydrochloricacid and acetic acid. The precipitates of crystals was taken out andwashed with water, dried, to obtain 400 mg of the intended compound.

EXAMPLE 13

According to-one of the foregoing Examples and Preparation Examples, thefollowing compounds were obtained. ##STR210##

NMR (400 MHz, DMSO--d₆, δ value): 8.50 (1H, d, J=5 Hz), 7.64˜7.51 (4H,m), 7.48 (1H, dd, J=1 Hz, 5 Hz), 7.17 (2H, d, J=8 Hz), 7.04 (2H, d, J=8Hz), 5.82 (2H, s), 3.52 (2H, q, J=7 Hz), 2.66 (3H, s), 1.22 (3H, t, J=7Hz) ##STR211##

NMR (400 MHz, DMSO--d₆, δ value): 8.0 (1H, d, J=5 Hz), 7.64 (2H, d, J=8Hz), 7.56 (1H, td, J=8 Hz, 1 Hz), 7.51 (1H, d, J=8 Hz), 7.16 (2H, d, J=8Hz), 7.04 (2H, d, J=8 Hz), 7.01 (1H, d, J=5 Hz), 5.23 (2H, s), 4.14 (3H,s), 2.48 (3H, s) ##STR212##

NMR (400 MHz, DMSO--d₆, δ value): 7.99 (1H, d, J=5 Hz), 7.65 (2H, d, J=8Hz), 7.56 (1H, t, J=8 Hz), 7.51 (1H, d, J=8 Hz), 7.18 (2H, d, J=8 Hz),7.04 (2H, d, J=8 Hz), 7.00 (1H, d, J=5 Hz), 5.21 (2H, 4.57 (2H, q, J=7Hz), 2.46 (3H, s), 1.37 (3H, t, J=7 Hz) ##STR213##

NMR (400 MHz, DMSO--d₆, δ value): 8.00 (1H, d, J=5 Hz), 7.65 (2H, dd,J=8 Hz, 1 Hz), 7.57 (1H, td, J=8 Hz, 1 Hz), 7.51 (1H, d, J=8 Hz), 7.20(2H, d, J=8 Hz,), 7.05 (2H, d, J=8 Hz), 7.00 (1H, d, J=5 Hz), 5.24 (2H,s), 4.48 (2H, t, J=7 Hz), 2.47 (3H, s), 1.81˜1.73 (2H, m), 0.93 (3H, t,J=7 Hz) ##STR214##

NMR (400 MHz, DMSO--d₆, δ value): 8.00 (1H, d, J=5 Hz), 7.65 (2H, dd,J=8 Hz, 1 Hz), 7.56 (1H, td, J=8 Hz, 1 Hz), 7.18 (2H, d, J=8 Hz), 7.04(2H, d, J=8 Hz), 7.00 (1H, d, J=5 Hz), 5.21 (2H, s), 4.52 (2H; t, J=7Hz), 2.47 (3H, s), 1.77˜1.70 (2H, m), 1.41˜1.32 (2H, m), 0.90 (3H, t,J=7 Hz) ##STR215##

NMR (400 MHz, DMSO--d₆, δ value): 7.98 (1H, d, J=5 Hz), 7.64 (2H, d, J=8Hz), 7.56 (1H, t, J=8 Hz), 7.51 (1H, d, J=8 Hz), 7.18 (2H, d, J=8 Hz),7.04 (2H, d, J=8 Hz), 6.99 (1H, d, J=5 Hz), 5.35˜5.30 (1H, m), 5.18 (2H,s), 2.47 (3H, s), 1.36 (6H, d, J=6 Hz) ##STR216##

NMR (400 MHz, DMSO--d₆, δ value): 7.99 (1H, d, J=5 Hz), 7.64 (2H, d, J=8Hz), 7.55 (1H, t, J=8 Hz), 7.50 (1H, d, J=8 Hz), 7.21 (2H, d, J=7 Hz),7.05 J=6 Hz) (2H, d, J=7 Hz), 6.99 (1H, d, J=5 Hz), 5.23 (2H, s), 4.38(2H, d, J=8 Hz), 2.46 (3H, s), 1.36˜1.25 (1H, 0.63˜0.50 (2H, m),0.41˜0.35 (2H, m) ##STR217##

NMR (400 MHz, DMSO--d₆. δ value): 11.36 (1H, s), 7.83 (1H, d, J=5 Hz),7.66 (1H, dd, J=8 Hz, 1 Hz), 7.65 (1H, d, J=8 Hz), 7.56 (1H, td, J=8 Hz,1 Hz), 7.52 (1H, d, J=8 Hz), 7.23 (2H, d, 3.81 Hz), 7.04 (2H, d, J=8Hz), 6.89 (1H, d, J=5 Hz), 5.00 (2H, s), 2.31 (3H, s) ##STR218##

NMR (400 MHz, DMSO--d₆, δ value): 8.19 (1H, d, J=5 Hz), 7.61 (2H, t, J=8Hz), 7.52 (1H, t, J=8 Hz), 7.47 (1H, d, J=8 Hz), 7.14 (2H, d, J=8 Hz),7.11 (1H, d, J=5 Hz), 7.03 (2H, d, J=8 Hz), 5.56 (2H, s), 4.67 (2H, s),2.55 (3H, s) ##STR219##

NMR (400 MHz, DMSO--d₆, δ value): 9.15 (1H, s), 8.92 (1H, s), 8.72 (1H,s), 7.61 (2H, d, J=7 Hz), 7.53 (1H, d, J=7 Hz), 7.46 (1H, d, J=7 Hz),7.24 (2H, d, J=7 Hz), 7.03 (2H, d, J=7 Hz), 5.48 (2H, s) ##STR220##

NMR (400 MHz, DMSO--d₆, δ value): 9.07 (1H, s), 8.90 (1H, s), 7.66 (2H,d, J=8 Hz), 7.57 (1H, t, J=8 Hz), 7.52 (1H, d, J=8 Hz), 7.14 (2H, d, J=8Hz), 7.07 (2H, d, J=8 Hz), 5.52 (2H, s), 2.84 (2H, t, J=8 Hz), 1.78˜1.69(2H, m), 0.93 (3H, t, J=8 Hz) ##STR221##

NMR (400 MHz, DMSO--d₆, δ value): 8.18 (1H, d, J=5 Hz), 7.66 (1H, dd,J=8 Hz, 1 Hz), 7.51 (1H, td, J=8 Hz, 1 Hz), 7.40 (1H, td, J=8 Hz, 1 Hz),7.30 (1H, dd, J=8 Hz, 1 Hz), 7.23 (4H, s), 7.09 (1H, d, J=5 Hz), 5.57(2H, s), 4.70 (2H, s), 2.54 (3H, s) ##STR222##

NMR (400 MHz, DMSO--d₆, δ value): 8.27 (1H, d, J=5 Hz), 7.68˜7.64 (2H,m), 7.56 (1H, t, J=8 Hz), 7.51 (1H, d, J=8 Hz), 7.18 (1H, d, J=5 Hz),7.18 (2H, d, J=8 Hz), 7.04 (2H, d, J=8 Hz), 5.60 (2H, s), 5.05 (2H, s),2.60 (3H, s) ##STR223##

NMR (400 MHz, DMSO--d₆, δ value): 7.63 (1H, td, J=8 Hz, 1 Hz), 7.61 (1H,rid, J=8 Hz, 1 Hz), 7.54 (1H, td, J=8 Hz, 1Hz), 7.48 (1H, rid, J=8 Hz, 1Hz), 7.01 (4H, s), 6.91 (1H, s), 5.43 (2H, s), 2.68 (2H, t, J=8 Hz),2.47 (6H, s), 1.68˜1.59 (2H, m), 0. 87 (3H, t, J=8 Hz) ##STR224##

NMR (400 MHz, DMSO--d₆, δ value): 7.60 (1H, d, J=8 Hz), 7.45 (1H, t, J=8Hz), 7.37 (1H, t, J=8 Hz), 7.27 (1H, d, J=8 Hz), 7.26 (2H, d, J=8 Hz),7.08 (2H, d, J=8 Hz), 6.92 (1H, ), 5.46 (2H, s), 2.73 (2H, t, J=8 Hz),2.49 (6H, s), 1.74˜1.65 (2H, m), 0.89 (3H, t, J=8 Hz) ##STR225##

NMR (400 MHz, DMSO--d₆, δ value): 9.08 (1H, s), 8.91 (1H, s), 7.71 (1H,d, J=8 Hz), 7.55 (1H, t, J=8 Hz), 7.44 (1H, t, J=8 Hz), 7.34 (1H, d, J=8Hz), 7.30 (2H, d, J=8 Hz), 7.23 (2H, d, J=8 Hz), 5.54 (2H, s), 2.89 (2H,t, J=8 Hz), 1.81˜1.75 (2H, m), 0.95 (3H, t, J=8 Hz) ##STR226##

NMR (400 MHz, DMSO--d₆, δ value): 7.67 (1H, td, J=8 Hz, 1 Hz), 7.65 (1H,d, J=8 Hz), 7.57 (1H, td, J=8 Hz, 1 Hz), 7.52 (1H, d, J=8 Hz), 7.12 (2H,d, J=8 Hz), 7.05 (2H, d, J=8 Hz), 6.92 (1H, s), 5.54 (2H, s), 2.49 (3H,s), 2.44 (3H, s), 2.17˜2.11 (1H, m), 0.99˜0.95 (4H, m) ##STR227##

NMR (400 MHz, DMSO--d₆, δ value): 7.71 (1H, dd, J=8 Hz, 1 Hz), 7.55 (1H,td, J=8 Hz, 1Hz), 7.44 (1H, td, J=8 Hz, 1 Hz), 7.34 (1H, dd, J=8 Hz, 1Hz), 7.29 (2H, d, J=8 Hz), 7.23 (2H, d, 6.95 (1H, s), 5.60 (2H, s), 2.49(3H, s), 2.45 (3H, s), 2.25˜2.18 (1H, m), 1.05˜1.00 (4H, m) ##STR228##

NMR (400 MHz, DMSO--d₆, δ value): 8.12 (d. 1H, J=5 Hz), 7.66˜7.60 (m.2H), 7.54 (td, 1H, J=8 Hz, 1Hz), 7.49 (dd, 1H, J=8 Hz, 1 Hz), 7.08 ((d,2H, J=8 Hz), 7.05 (d, 1H, J=5 Hz), 7.02 (d, 2H, J=8 Hz), 5.45 (s, 2H),2.52 (s, 3H), 2.48 (s, 3H) ##STR229##

NMR (400 MHz, DMSO--d₆, δ value): 8.54 (s, 1H), 8.23 (d, 1H, J=5 Hz),7.68˜7.62 (m, 2H), 7.56 (td, 1H, J=8 Hz, 1 Hz), 7.49 (d, 1H, J=8 Hz),7.24 (d, 2H, J=8 Hz), 7.12 (d, 1H, J=5 Hz), 7.05 (d, 2H, J=8 Hz), 5.49(s, 2H), 2.58 (s, 3H) ##STR230##

NMR (400 MHz, CDCl₃, δ value): 8.22 (d, 1H, J=5 Hz), 7.74 (d, 1H, J=8Hz), 7.62 (td, 1H, J=8 Hz, 1 Hz), 7.51˜7.40 (m, 4H), 7.27 (d, 2H, J=8Hz), 7.05 (d, 1H, J=5 Hz), 5.54 (s, 2H), 2.69 (s, 3H), 2.60 (s, 3H)##STR231##

NMR (400 MHz, CDCl₃, δ value): 8.32 (d, 1H, J=5 Hz), 8.24˜8.17 (bs, 1H),7.40 (d, 1H, J=8 Hz), 7.63 (td, 1H, J=8 Hz, 1 Hz), 7.52 (d, 2H, J=8 Hz),7.48˜7.39 (m, 4H), 7.11 (d, 1H, J=5 Hz), 5.59 (s, 2H), 2.72 (s, 3H)##STR232##

NMR (400 MHz, CDCl₃, δ value): 8.16 (d, 1H, J=5 Hz), 7.02 (d, 1H, J=5Hz), 2.73 (s, 3H), 2.68 (s, 3H) ##STR233##

NMR (400 MHz, CDCl₃, δ value): 8.30 (d, 1H, J=5 Hz), 8.28 (s, 1H), 7.09(d, 1H, J=5 Hz), 2.70 (s, 3H) ##STR234##

NMR (400 MHz, CDCl₃, δ value): 8.36 (dd, 1H, J=1 Hz, 5 Hz), 8.03 (dd,1H, J=1 Hz, 8 Hz), 7.81 (dd, 1H, J=1 Hz, 8 Hz), 7.51 (td, 1H, J=8 Hz, 1Hz), 7.40 (td, 1H, J=8 Hz, 1 Hz), 7.31 (dd, 1H, J=1 Hz, 8 Hz), 7.24 (d,2H, J=8 Hz), 7.23 (dd, 1H, J=5 Hz, 8 Hz), 7.18 (d, 2H, J=8 Hz), 5.54 (s,2H), 3.61 (s, 3H), 2.87 (q, J=8 Hz), 1.41 (t, 3H, J=8 Hz) ##STR235##

NMR (400 MHz, CDCl₃, δ value: 8.33 (dd, 1H, J=1 Hz, 5 Hz), 7.95 (dd, 1H,J=1 Hz, 8 Hz), 7.82 (dd, 1H, J=1 Hz, 8 Hz), 7.52 (td, 1H, J=8 Hz, 1 Hz),7.41 (td, 1H, J=8 Hz, 1 Hz), 7.33 (dd, 1H, J=1 Hz, 8 Hz), 7.27 (s, 4H),7.21 (dd, 1H, J=5 Hz, 8 Hz), 5.67 (s, 2H), 3.63 (s, 3H), 2.06˜1.96 (m,1H), 1.28˜1.21 (m, 2H), 1.11˜1.04 (m, 2H) ##STR236##

NMR (400 MHz, CDCl₃, δ0 value): 8.46 (dd, 1H, J=1 Hz, 5 Hz), 7.84 (dd,1H, J=1 Hz, 8 Hz), 7.55˜7.49 (m, 2H), 7.41 (td, 1H, J=8 Hz, 1 Hz), 7.31(dd, 1H, J=1 Hz, 8 Hz), 7.28 (d, 2H, J=8 Hz), 7.15 (d, 2H, J=8 Hz), 7.09(dd, 1H, J=5 Hz, 8 Hz), 5.51 (s, 2H), 3.64 (s, 3H), 2.07˜1.95 (m, 2H),1.43˜1.35 (m, 2H), 1.16˜1.08 (m, 2H), ##STR237##

NMR (400 MHz, CDCl₃, δ value): 8.19 (d, 1H, J=5 Hz), 7.70 (d, 1H, J=5Hz), 7.37 (dd, 1H, J=2 Hz, 8 Hz), 7.31 (d, 1H, J=2 Hz), 7.25˜7.20 (m,4H), 7.01 (d, 1H, J=5 Hz), 5.63 (s, 2H), 3.61 (s, 3H), 2.65 (s, 3H),2.00˜1.92 (m, 1H), 1.24˜1.17 (m, 2H), 1.08˜1.00 (m, 2H) ##STR238##

NMR (400 MHz, CDCl₃, δ value): 7.95 (d, 1H, J=8 Hz), 7.82 (dd, 1H, J=1Hz, 8 Hz), 7.51 (td, 1H, J=8 Hz, 1 Hz), 7.40 (td, 1H, J=8 Hz, 1 Hz),7.31 (dd, 1H, J=1 Hz, 8 Hz), 7.25 (d, 2H, J=8 Hz), 7.23 (d, 1H, J=5 Hz),7.17 (d, 2H, J=5 Hz), 5.49 (s, 2H), 3.62 (s, 3H), 2.83 (q, 2H, J=8 Hz),1.39 (t, 3H, J=8 Hz) ##STR239##

NMR (400 MHz, CDCl₃, δ value): 7.86 (d, 1H, J=8 Hz), 7.53 (td, 1H, J=8Hz, 1 Hz), 7.46 (d, 1H, J=8 Hz), 7.42 (td, 1H, J=8 Hz, 1 Hz), 7.32 (d,1H, J=8 Hz), 7.27 (d, 2H, J=8 Hz), 7.14 (d, 1H, J=8 Hz), 7.06 (d, 2H,J=8 Hz), 5.38 (s, 2H), 3.65 (s, 3H), 2.93 (q, 2H, J=8 Hz), 1.46 (t, 3H,J=8 Hz) ##STR240##

NMR (400 MHz, CDCl₃, δ value): 8.40 (d, 1H, J=2Hz), 8.14 (d, 1H, J=2Hz),7.83 (dd, 1H, J=1 Hz, 8 Hz), 7.51 (td, 1H, J=8 Hz, 1 Hz), 7.40 (td, 1H,J=8 Hz, 1 Hz), 7.30 (dd, 1H, J=1 Hz, 8 Hz), 7.25 (d, 2H, J=8 Hz), 7.17(d, 2H, J=8 Hz), 5.50 (s, 2H), 3.62 (s, 3H), 2.87 (q, 2H, J=8 Hz), 1.40(t, 3H, J=8 Hz) ##STR241##

NMR (400 MHz, CDCl₃, δ value): 8.18 (d, 1H, J=2 Hz), 7.82˜7.19 (m, 2H),7.51 (td, 1H, J=8 Hz, 1 Hz), 7.40 (td, 1H, J=8 Hz, 1 Hz), 7.30 (dd, 1H,J=1 Hz, 8 Hz), 7.23 (d, 2H, J=8 Hz), 7.15 (d, 2H, J=8 Hz), 5.51 (s, 2H),3.61 (s, 3H), 2.80 (t, 2H, J=8 Hz), 2.48 (s, 3H), 1.90˜1.78 (m, 2H),1.00 (t, 3H, J=8 Hz) ##STR242##

NMR (400 MHz, CDCl₃, δ value): 8.28 (s, 1H), 7.82 (dd, 1H, J=1 Hz, 8Hz), 7.51 (td, 1H, J=8 Hz, 1 Hz), 7.41 (td, 1H, J=8 Hz, 1Hz), 7.31 (dd,1H, J=1 Hz, 8 Hz), 7.25 (d, 2H, J=8 Hz), 7.15 (d, 2H, J=8 Hz), 5.50 (s,2H), 3.62 (s, 3H), 2.83 (t, 2H, J=8 Hz), 2.72 (s, 3H), 1.87˜1.75 (m,2H), 1.01 (t, 3H, J=8 Hz) ##STR243##

NMR (400 MHz, CDCl₃, δ value): 8.30 (d, 1H, J=5 Hz), 7.83 (dd, 1H, J=1Hz, 8 Hz), 7.52 (td, 1H, J=8 Hz, 1 Hz), 7.41 (td, 1H, J=8 Hz, 1Hz), 7.32(dd, 1H, J=1 Hz, 8 Hz), 7.27 (d, 2H, J=8 Hz), 7.02 (d, 2H, J=8 Hz), 6.83(d, 1H, J=5 Hz), 5.71 (s, 2H), 3.63 (s, 3H), 2.48 (s, 3H), 1.98˜1.89 (m,1H), 1.39˜1.32 (m, 2H), 1.11˜1.03 (m, 2H) ##STR244##

m.p.: 235°˜238° C.

NMR (400 MHz, DMSO--d₆, δ value): 8.32 (dd, 1H, J=1 Hz, 5 Hz), 8.20 (dd,1H, J=1 Hz, 8 Hz), 7.70 (dd, 1H, J=1Hz, 8 Hz), 754 (td, 1H, J=8 Hz, 1Hz), 7.44 (td, 1H, J=8 Hz, 1 Hz), 7.34 (dd, 1H, J=1 Hz, 8 Hz), 7.30˜7.24(m, 3H), 7.20 (d, 2H), 5.56 (s, 2H), 2.89 (q,2H, J=8 Hz), 1.29 (t, 3H,J=8 Hz) ##STR245##

m.p.: 246.5°˜248.5° C.

NMR (400 MHz, DMSO--d₆, δ value): 8.27 (dd, 1H, J=1 Hz, 5 Hz), 7.92 (dd,1H, J=1 Hz, 8 Hz), 7.71 (dd, 1H, J=1 Hz, 8 Hz), 7.54 (td, 1H, J=8 Hz, 1Hz), 7.43 (td, 1H, J=8 Hz, 1 Hz), 7.34 (dd, 1H, J=1 Hz, 8 Hz), 7.29 (s,4H), 7.23 (dd, 1H, J=5 Hz, 8 Hz), 5.67 (s, 2H), 2.37˜2.19 (m, 1H),1.13˜1.02 (m, 4H) ##STR246##

m.p.: 227°˜229° C.

NMR (400 MHz, DMSO--d₆, δ value): 8.31 (dd, 1H, J=1 Hz, 5 Hz), 7.94 (dd,1H, J=1 Hz, 8 Hz), 7.71 (dd, 1H, J=1 Hz, 8 Hz), 7.54 (td, 1H, J=8 Hz, 1Hz), 7.43 (td, 1H, J=8 Hz, 1 Hz), 7.34 (dd, 1H, J=1 Hz, 8 Hz), 7.31 (d,2H, J=8 Hz), 7.24 (d, 2H, J=8 Hz), 7.17 (dd, 1H, J=5 Hz, 8 Hz), 5.69 (s,2H), 2.41˜2.33 (m, 1H), 1.19˜1.06 (m, 4H) ##STR247##

m.p.: 256°˜259° C.

NMR (400 MHz, DMSO--d₆, δ value): 8.13 (d, 1H, J=5 Hz), 7.74 (d, 1H, J=8Hz), 7.51 (dd, 1H, J=2Hz, 8 Hz), 7.40 (d, 1H, J=2Hz), 7.31 (d, 2H, J=8Hz), 7.27 (d, 2H, J=8 Hz), 7.05 (d, 1H, J=5 Hz), 5.65 (s, 2H), 2.51 (s,3H), 2.32˜2.24 (m, 1H), 1.08˜1.00 (m, 4H) ##STR248##

m.p.: 248°˜251° C.

NMR (400 MHz, DMSO--d₆, δ value): 12.75 (bs, 1H), 8.10 (d, 1H, J=8 Hz),7.72 (d, 1H, J=8 Hz), 7.55 (t, 1H, J=8 Hz), 7.44 (t, 1H, J=8 Hz),7.37˜7.32 (m, 2H), 7.31 (d, 2H, J=8 Hz), 7.18 (d, 2H, J=8 Hz), 5.53 (s,2H), 2.87 (q, 2H, J=8 Hz), 1.28 (t, 3H, J=8 Hz) ##STR249##

m.p.: 280°˜282° C.

NMR (400 MHz, DMSO--d₆, δ value): 12.74 (bs, 1H), 8.06 (d, 1H, J=8 Hz),7.71 (dd, 1H, J=1 Hz, 8 Hz), 7.55 (td, 1H, J=8 Hz, 1 Hz), 7.44 (td, 1H,J=8 Hz, 1 Hz), 7.33 (dd, 1H, J=1 Hz, 8 Hz), 7.32˜7.28 (m, 3H), 7.16 (d,2H, J=8 Hz), 5.60 (s, 2H), 2.93 (q, 2H, J=8 Hz), 1.30 (t, 3H, J=8 Hz)##STR250##

m.p.: 235°˜237° C.

NMR (400 MHz, DMSO--d₆, δ value): 8.42 (d, 1H, J=2 Hz), 8.22 (d, 1H, J=2Hz), 7.71 (dd, 1H, J=1 Hz, 8 Hz), 7.55 (td, 1H, J=8 Hz, 1 Hz), 7.44 (td,1H, J=8 Hz, 1 Hz), 7.32 (dd, 1H, J=1 Hz, 8 Hz), 7.28 (d, 2H, J=8 Hz),7.20 (d, 2H, J=8 Hz), 5.55 (s, 2H), 2.91 (q, 2H, J=8 Hz), 1.28 (t, 3H,J=8 Hz) ##STR251##

m.p.: 208°˜210° C.

NMR (400 MHz, DMSO--d₆, δ value): 8.16 (d, 1H, J=2 Hz), 7.83 (d, 1H, J=2Hz), 7.70 (dd, 1H, J=1 Hz, 8 Hz), 7.54 (td, 1H, J=8 Hz, 1 Hz), 7.43 (td,1H, J=8 Hz, 1 Hz), 7.22 (dd, 1H, J=1 Hz, 8 Hz), 7.27 (d, 2H, J=8 Hz),7.17 (d, 2H, J=8 Hz), 5.53 (s, 2H), 2.82 (t, 2H, J=8 Hz), 2.42 (s, 3H),1.80˜1.70 (m, 2H), 0.94 (t, 3H, J=8 Hz) ##STR252##

m.p.: 189°˜191° C.

NMR (400 MHz, DMSO--d₆, δ value): 12.73 (bs, 1H), 8.31 (s, 1H), 7.71(dd, 1H, J=1 Hz, 8 Hz), 7.55 (td, 1H, J=8 Hz, 1Hz), 7.44 (td, 1H, J=8Hz, 1 Hz), 7.33 (dd, 1H, J=1 Hz, 8 Hz), 7.28 (d, 2H, J=8 Hz), 7.18 (d,2H, J=8 Hz), 5.55 (s, 2H), 2.85 (t, 2H, J=8 Hz), 2.61 (s, 3H), 1.80˜1.69(m, 2H), 0.95 (t, 3H, J=8 Hz) ##STR253##

NMR (400 MHz, DMSO--d₆, δ value): 8.16 (d, 1H, J=5 Hz), 7.70 (d, 1H, J=8Hz), 7.54 (t, 1H, J=8 Hz), 7.43 (t, 1H, J=8 Hz), 7.35 (d, 1H, J=8 Hz),7.32 (d, 2H, J=8 Hz), 7.02 (d, 2H, J=8 Hz), 6.90 (d, 1H, J=5 Hz), 5.83(s, 2H), 2.44 (s, 3H), 2.31˜2.23 (m, 1H), 1.15˜1.02 (m, 4H)

We claim:
 1. A compound having the formula ##STR254## or apharmacologically acceptable salt thereof.
 2. A pharmacologicalcomposition comprising an antihypertensive or anticardiac failing amountof the biphenylmethane derivative or a pharmacologically acceptable saltthereof as defined in claim 1 and a pharmacologically acceptablecarrier.
 3. A method for preventing and treating hypertension byadministering an effective antihypertensive amount of thebiphenylmethane derivative or a pharmacologically acceptable saltthereof as defined in claim 1 to a patient in need thereof.
 4. A methodfor preventing and treating cardiac failure by administering aneffective anticardiac failing amount of the biphenylmethane derivativeor a pharmacologically acceptable salt thereof as defined in claim 1 toa patient in need thereof.